review article mechanisms of omega-3 polyunsaturated fatty...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 824563 10 pageshttpdxdoiorg1011552013824563

Review ArticleMechanisms of Omega-3 Polyunsaturated Fatty Acids inProstate Cancer Prevention

Zhennan Gu12 Janel Suburu2 Haiqin Chen1 and Yong Q Chen12

1 State Key Laboratory of Food Science and Technology School of Food Science and Technology Jiangnan UniversityWuxi 214122 China

2Department of Cancer Biology Wake Forest University School of Medicine Medical Center Boulevard Winston-SalemNC 27157 USA

Correspondence should be addressed to Yong Q Chen yqchenwakehealthedu

Received 6 March 2013 Revised 2 May 2013 Accepted 8 May 2013

Academic Editor Gabriella Calviello

Copyright copy 2013 Zhennan Gu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

This review focuses on several key areas where progress has been made recently to highlight the role of omega-3 polyunsaturatedfatty acid in prostate cancer prevention

1 Introduction

The health benefits of omega-3 polyunsaturated fatty acids(n-3 PUFA) mainly eicosapentaenoic acid (EPA 205) anddocosahexaenoic acid (DHA 226) have been long knownEpidemiologic studies dating back to the 1970s were amongthe first to suggest that dietary PUFA may be beneficialin preventing disease [1 2] Still today studies continue todemonstrate the health benefits of n-3 PUFA however themechanisms of action of n-3 PUFA are still not fully under-stood Many new discoveries have advanced our understand-ing about the activities of n-3 PUFA against human diseaseFor example DHA-receptor GPR120 has been demonstratedto play a role in sensing and controlling obesity andmetabolicsyndrome [3] the recently identified omega-3 mediatorsresolvins and protectins have been demonstrated to haveanti-inflammatory and proresolving activities [4] The pur-pose of this review is to highlight the recent advances inour understanding of the mechanisms by which n-3 PUFAmodulate prostate cancer development

2 Fatty Acids

There are two major classes of PUFA n-6 and n-3 Unlikesaturated and monounsaturated fatty acid PUFA cannotbe synthesized de novo by mammals because they lack the

required enzymes and therefore PUFA must be obtainedfrom the dietThe n-6 and n-3 PUFA also cannot be intercon-verted in mammals but within each series their metabolismcan produce various lipids that differ in chain length andnumber of double bonds Linoleic acid (LA 182 n-6) is an n-6PUFA found in high concentration in grains as well as manyseeds and meats LA serves as a substrate to be convertedinto a longer fatty acid arachidonic acid (AA 204 n-6) viaa series of oxidative desaturation and elongation reactionsOf the n-3 fatty acids alpha linolenic acid (ALA 183 n-3)is found at moderate levels in plants seeds leafy vegetableslegumes and nuts ALA is not metabolized efficiently tolonger-chain n-3 PUFA such as EPA and DHA

Although they belong to two distinct families n-3 andn-6 PUFA are metabolized by some of the same enzymesspecifically delta-5-desaturase anddelta-6-desaturase Excessin one family of fatty acid can interferewith themetabolismofthe other and alter their overall biological effects [5] Duringn-6 PUFA conversion delta-6-desaturase or fatty acid desat-urase 2 (FADS2) converts LA to gamma-linolenic acid (GLA183 n-6) This enzyme represents a rate-limiting step in thesynthesis of AA from LA [6] GLA is elongated to dihomo-gamma-linolenic acid (DGLA 203 n-6) through a chainreaction of four enzymes a condensation reaction of thefatty acyl chain with malonyl-CoA catalyzed by an enzymeencoded by the ELOVL5 gene (elongation of very long-chain

2 BioMed Research International

fatty acids family member 5) a reduction reaction mediatedby 3-ketoacyl-CoA reductase (KAR) a dehydration reactioncatalyzed by 3-hydroxyacyl-CoA dehydratase (HACD) anda second reduction reaction catalyzed by trans-23-enoyl-CoA reductase (TECR) Finally DGLA is converted to AAby delta-5 desaturase or fatty acid desaturase 1 (FADS1) [6 7]Interestingly malonyl-CoA which is necessary for fatty acidelongation is derived from the rate-limiting enzyme of thede novo fatty acid synthesis pathway acetyl-CoA carboxylaseFatty acid synthesis is well described as an overactive pathwayin many cancers [8ndash11] and its upregulation may also con-tribute to the elongation of PUFA

In contrast to AA the efficiency of ALA conversion toDHA appears to be very low below 5 in humans Mostingested ALA is subject to beta-oxidation to provide energyand only a small fraction is converted to EPA [12 13] Itwas estimated that as low as 02 of ALA is converted toEPA 64 of EPA to docosapentaenoic acid (DPA 225 n-3)and 37 of DPA to DHA [14] Thus the overall amountof DPA and DHA converted from ALA is about 013and 005 of the starting ALA respectively These findingssuggest that any contributions from the fatty acid synthesispathway toward PUFA metabolism most likely favor n-6rather than n-3 PUFA elongation It is also very likely thatsynthesis of the longer n-3 fatty acids from ALA within thebody is competitively hindered by the n-6 analogues It hasbeen reported that the n-3 conversion efficiency is greater inwomen possibly because of the importance of meeting theDHA demands of the fetus and neonate [14]

3 PUFA and Cancer

Total fat intake and the ratio of n-6 to n-3 PUFA in theWestern diet have increased significantly since the IndustrialRevolution [15 16] Increased fat consumption has been asso-ciated with the development of specific types of cancer suchas breast colon and pancreatic and prostate cancers with thenotable exception of n-3 PUFA which show protective effectsagainst colon breast and prostate cancers in a number ofexperimental systems [17ndash23] Epidemiological studies aboutthe association of dietary fat and cancer suggests a protectiveeffect of n-3 PUFA and a promoting effect of n-6 PUFA oncancer Most clinical data regarding the effects of dietary faton cancers are observational [24] and the results of suchstudies are mixed as many fail to demonstrate a significantassociation between n-3 PUFA and reduced prostate cancerrisk or tumor growth [20 25ndash27]

The Western diet contains disproportionally highamounts of n-6 PUFA and low amounts of n-3 PUFAdenoted as a high n-6 to n-3 PUFA ratio Most data regardingthe effects of high dietary n-6 PUFA are positively associatedwith prostate cancer incidence [28ndash30] In a study ofJamaican men undergoing prostate biopsy for elevated PSAlevels a positive correlation was observed between n-6 fattyacid LA and Gleason score and n-6 (LA) to n-3 (DHA)ratio in erythrocyte membranes and prostate tumor volume[31] By comparing PUFA content from malignant andbenign prostatic tissues from the same prostate specimens

a Swedish research group found that n-6 PUFA and n-6PUFA precursors were significantly higher in malignanttissues This finding further demonstrates that n-6 dietaryfat is associated with prostate carcinogenesis [28] In race-specific analyses based on a case-control study comprising79 prostate cancer cases and 187 controls Williams andcolleagues found that a high ratio of n-6 to n-3 fatty acidsmay increase the overall risk of prostate cancer among whitemen and possibly increase the risk of high-grade prostatecancer among all men [29]

At the same time epidemiological literature on theassociation of n-3 PUFA and cancer including correlationalstudies and migrational studies suggest a protective roleplayed by n-3 PUFA In a recent population-based prospec-tive cohort study of 90296 Japanese subjects Sawada et alreported that consumption of n-3-rich fish or n-3 PUFAparticularly EPA DPA and DHA appears to protect againstthe development of hepatocellular carcinoma (HCC) [32] Inanother population-based prospective study in Japan therewas an inverse relationship between marine n-3 PUFA intakeand the risk of colorectal cancer but this association wasonly statistically significant in the proximal site of the largebowel [33] Chavarro et al performed a nested case-controlstudy by analyzing blood samples of 14916 healthy men andconcluded that higher blood levels of long-chain n-3 fattyacids were associated with a reduced risk of prostate cancer[34] Szymanski et al conducted ameta-analysis of fish intakeand prostate cancer by focusing on the incidence of prostatecancer and prostate cancer-specific mortality Their resultsdid not establish a protective association of fish consumptionwith prostate cancer incidence but showed a significant 63reduction in prostate cancer-specific mortality [35]

The results of correlational studies are mixed someof them failing to demonstrate a statistically significanteffect Several confounding factors could account for theinconsistent results on the association between n-3 PUFAand prostate cancer First population-based studies mainlyrely on data from self-reported dietary fatty acid intake orfrom estimates based on national consumption and theseassessments correlate poorly with direct measurements offatty acids in patient samples In addition the actual intakein n-3 PUFA may be too low for a protective effect in somecases Second the ratio of n-6 to n-3 fatty acids may bemore important than the absolute amount of n-3 PUFAas suggested by animal and human studies [16 36] Usinga prostate-specific Pten knockout mouse prostate cancermodel we showed that a ratio of n-6 to n-3 below 5 waseffective in slowing cancer progression [3] Brown et alreported that AA might potentiate the risk of metastaticprostate cancer cell migration and seeding at the secondarysite in vivo and lowering the n-6n-3 ratio in diet by uptakeof n-3 PUFA might reduce this risk [37]

4 Mechanisms of Action

41 Integration of PUFAs into PlasmaMembrane Glycerophos-pholipids Although fatty acids are consumed at high levelsin a typical Western diet tumor cells display a strong

BioMed Research International 3

dependence on de novo fatty acid synthesis [9 10] Theincreased proliferation and metabolism of cancer cells couldbe the trigger for the abnormal requirement for fatty acidcompared to normal cells Most newly synthesized fatty acidsare used to support membrane biogenesis in the form ofglycerophospholipids a class of lipids that are amajor compo-nent of all cell membranes Glycerophospholipids includingphosphatidylcholine (PC) phosphatidylserine (PS) phos-phatidylethanolamine (PE) and phosphatidylinositol (PI)contain a diglyceride a phosphate group and a simpleorganic molecule such as choline or serine

Dietary PUFA can influence the fatty acid compositionof glycerophospholipids in cell membranes In mammals thesn-1 position on the glycerol backbone of glycerophospho-lipids is usually linked to a saturated fatty acid such as stearicacid (SA 180) and the sn-2 position is linked to ann-6 PUFAsuch as AA Feeding cells in culture or animals with n-3PUFA can replace n-6 with n-3 fatty acid at the sn-2 positionof glycerophospholipids this is considered a diet-induced sn-2 fatty acid moiety change [17 38 39] We have analyzed theincorporation efficiency of PUFAs into glycerophospholipidsin prostate cancer cells Approximately 25of input albumin-conjugated fatty acids were incorporated into cells within 48hours The majority of these newly integrated PUFAs were inthe form of PC and PE [40] These data clearly suggest thatthe fatty acid at the sn-2 position of glycerophospholipids isinfluenced by cellular PUFA uptake

n-3 PUFA influences cell membrane conformation andsignaling dynamics The greater density of n-3 PUFA com-pared to n-6 PUFA dictates their aggregation near the lipid-water interface This characteristic can significantly affectplasma membrane properties including membrane fluidityphase behavior and permeability [41] These membrane per-turbations can bring about changes associated with receptoractivation such as diffusional coupling of various peripheralproteins required in G protein-coupled receptor signaling(GPCR) [42 43] Additionally because of its high level ofunsaturation DHA has very poor affinity for cholesterolwhich is enriched in lipid rafts of the cell membrane Lipidrafts are important membrane domains for cell signaling asmany receptors and proteins are enriched in this domainsuch as epidermal growth factor receptor (EGFR) [44]Hence incorporation of n-3 PUFA into membrane lipidscan disturb the formation of lipid rafts and suppress raft-associated cell signal transduction [13 44]

The serinethreonine protein kinase AKT (protein kinaseB) is activated in many solid tumors and hematologicalmalignancies AKT acts downstream of phosphatidylinositol3-kinase (PI3K) signaling and is a key regulator of multiplesurvival pathways AKT is known to phosphorylate andinactivate the proapoptotic Bcl-2 family member BAD as oneof its prosurvival tactics [45] Phosphatidylinositol (PI) is anegatively charged constituent of lipid membranes Specifickinases phosphorylate the hydroxyl groups on positions 3101584041015840 or 51015840 of the inositol ring and PI3K primarily gener-ates PI-345-trisphosphate (PIP

3) from PI-45-bisphosphate

(PI(45)P2) PIP3acts as a secondmessenger to activate pleck-

strin homology (PH) domain-containing proteins includingAKT Conversely PIP

3is hydrolyzed to PI(45)P

2by PTEN

opposing the action of PI3K [46 47] AKT can also be phos-phorylated and activated by phosphoinositide-dependentkinase-1 (PDPK1) a PH domain-containing kinase down-stream of PI3K (for review see Franke 2008) [48] Henceintracellular PIP

3plays a pivotal role in this PI3KPIP

3AkT

cascade pathwayUsing prostate-specific Pten knockout mice an immune-

competent orthotopic prostate cancer model and diets withdefined PUFA levels we found that n-3 fatty acid reducedprostate tumor growth slowedhistopathological progressionand increased survival whereas n-6 fatty acid had oppositeeffects Introducing an n-3 desaturase which converts n-6to n-3 fatty acid into the Pten knockout mice fed an n-6diet reduced tumor growth similarly to mice fed the n-3 dietTumors from mice on the n-3 diet had lower proportions ofphosphorylated BADandhigher apoptotic indexes comparedwith tumors from mice on the n-6 diet These data suggestthat n-3 PUFA can promote BAD-dependent apoptosis tomodulate prostate cancer development [17] We also foundthat PUFAs modify glycerophospholipid content DHA canreplace the fatty acid at the sn-2 position of the glycerolbackbone thereby changing the species of phospholipidDHA also inhibited AKTT308 but not AKTS473 phosphoryla-tion altered PIP

3and phospho-AKTS473 protein localization

decreased pPDPK1S241-AKT and AKT-BAD interaction andsuppressed prostate tumor growth Knockdown of BADeliminated n-3 PUFA-induced cell death and reintroductionof BAD restored the sensitivity to n-3 fatty acids in vitroKnockout of BAD diminished the suppressive effect of n-3PUFA on prostate tumor growth in vivo These data suggestthat modulation of prostate cancer development by PUFA ismediated in part through the PI3KAKT survival pathway[17 40]

Hu et al reported that n-3 PUFA-induced apoptosis inhuman prostate cancer cells occurs through upregulationof syndecan-1 (SDC-1) expression followed by concomitantsuppression of PDPK1AKTBAD phosphorylation [49] n-3 fatty acids may also decrease cell proliferation and induceapoptotic cell death in human cancer cells by decreasingsignal transduction through the AKTNF120581B cell survivalpathway and by modulating the PI3KAKTp38 MAPKpathway [50 51]

42 PUFA Mediator A common fate of unsaturated lipidsreleased from themembrane is oxidation AA is the precursorof highly bioactive lipid mediators metabolized by a numberof enzymes belonging to the cyclooxygenase (COX) andlipoxygenase (LOX) families as well as cytochrome P450COXs have two well-characterized isoforms COX1 andCOX2 COX1 is a constitutively expressed gene in mosttissues whereas COX2 is an immediate-early response genewhich is strongly induced in many humanmalignancies [52]Signal transduction of n-6 PUFA-derived lipids and the effectof these lipid mediators on the organism have been wellcharacterized For example AA-derived lipid mediators areassociated with a variety of activities including inflammationand cancer Evidence from human studies also supports theimportant role of COXs and LOXs in PUFA metabolism and


cancer [53ndash56] Because of its high expression in inflamma-tion and cancer COX2 has been the subject of intense studyand proposed as a target for cancer therapy [57ndash59]

In contrast to n-6 PUFA the metabolism of n-3 PUFAis not well understood Interest in n-3 PUFA-derived lipidmediators began with observations of Greenland Eskimoswhose diet is rich in marine-derived fish and showed lowermortality from coronary heart disease and lower preva-lence of inflammation-related diseases such as psoriasisinflammatory bowel disease asthma rheumatoid arthritisand other autoimmune diseases [60 61] Serhan et alreported that inflammatory exudates in themurine air pouchfrom mice treated with n-3 PUFA and aspirin contained aseries of bioactive compounds Using an unbiased lipidomicsapproach they identified and named the EPA-derived E-resolvins (RvE1 and RvE2) DHA-derived D-resolvins (RvD1and RvD2) and (neuro-)protectin (PD1) [62]

RvE1 and RvE2 are protective in a wide variety of diseasemodels mainly through their anti-inflammatory activitiesRvE1 can resolve inflammation caused by bacterial infectionof periodontal disease in a rabbit model [63] prevent neo-vascularization after oxygen-induced retinopathy [64] andsuppress neutrophil infiltration in an acute peritonitis model[65] RvD1 RvD2 and PD1 also have protective activitiesin a variety of animal models including models of lunginjury insulin resistance peritonitis wound healing andatherosclerosis [66] RvD1 was shown to reduce leukocyteinfiltration in murine inflammatory exudates [67] and RvD2was shown to reverse inflammatory pain in mice [68] PD1has been reported to regulate amyloid beta secretion andthereby improve neuronal survival in a mouse model ofAlzheimerrsquos disease [69] Although ample data indicate thatthese n-3 PUFA-derivedmediators can resolve inflammationlittle is known about their role in inflammation-relatedcancers such as prostate and colon cancers

Due to the existence of multiple oxygenases the roleof each enzyme in the development of prostate cancer hasnot been studied systematically in a single system or animalmodel Furthermore studies performed in animals rarelytake diet into account To systematically assess the interactionbetween oxygenases and dietary PUFA in a single animalmodel of prostate cancer we knocked out Cox1 Cox2Lox5 Lox12 or Lox15 in prostate-specific Pten null miceOur preliminary results indicate that tumor growth wassignificantly increased in Cox1minusminus Pten null mice on n-3 dietcompared to Cox1-wild-type Pten null littermatesThis resultsuggests that Cox1 is required for the protective effects ofn-3 PUFA Interestingly tumor growth was decreased in n-6PUFA fed Cox1minusminus Pten-null mice compared to n-6 fed Cox1-wildtype Pten-null mice suggesting that n-6 metabolites ofCox1 promote tumor growth Loss of Cox2 reduced prostatetumor growth on both n-3 and n-6 diets suggesting thatthe suppressive effect of n-3 PUFA is independent of Cox2metabolism Loss of Lox5 reduced prostate tumor growthon n-6 diet but had no effect on n-3 diet loss of Lox12 orLox15 did not affect prostate tumor growth on either dietThese results suggest that the promotion of prostate tumorgrowth by n-6 diet is dependent on Lox-5 metabolism and

both Lox12 and Lox15 metabolites are not critical for prostatecancer growth in this model (Chen et al unpublished)

43 Fatty Acids Receptors Lipids are ligands for cell-sur-face G protein-coupled receptors (GPCRs) toll-like recep-tors (TLRs) and peroxisome proliferator-activated receptors(PPARs) G protein-coupled receptors (GPCRs) are impor-tant signalingmolecules formany aspects of cellular functionThey are members of a large family that share commonstructural motifs such as seven transmembrane helices andthe ability to activate heterotrimeric G proteins Recentlyseveral groups reported that unbound free fatty acids canactivate GPCRs including GPR40 GPR41 GPR43 GPR84and GPR120 [3] Short-chain fatty acids are specific ligandsfor GPR41 and GPR43 medium-chain fatty acids for GPR84and long-chain fatty acids for GPR40 and GPR120 [70ndash73]Activation of GPR84 receptor by medium-chain fatty acidstriggered the production of the proinflammatory cytokinesfrom leukocytes and macrophages The function of GPR84may be associated with chronic low-grade inflammation-associated disease [74]

GPR40 and GPR120 have been reported to be activatedby long-chain fatty acids such as DHA EPA and AA [73 75]As a G protein-coupled receptor GPR40 can activate thephospholipase C and phosphatidylinositol signaling path-ways [76] Although GPR40 is preferentially expressed inpancreatic 120573-cells and is known to mediate insulin secretion[77] several groups showed that it is expressed in thebrain where it mediates the antinociceptive activity of DHA[78 79] Recently Oh and others reported that GPR120functions as an n-3 PUFA receptor in vitro and in vivo [3]and suggested that diminished activation of GPR120 can bean important contributor to obesity insulin resistance andtissue inflammation [80 81] GPR120 is highly expressedin adipose tissue proinflammatory bone marrow-derivedCD11C+ macrophages (BMDCs) mature adipocytes andmonocytic RAW 2647 macrophage cells DHA stronglyinhibited LPS-induced phosphorylation of JNK and IKK120573I120581B degradation cytokine secretion- and inflammatory geneexpression level in GPR120-positive cells These effects ofDHA were completely prevented by GPR120 knockdowndemonstrating that these anti-inflammatory effects werespecifically exerted through GPR120 An n-3 PUFA dietcontaining 27 fish oil led to improved insulin sensitivitywith increased glucose infusion rates enhanced muscleinsulin sensitivity and greater hepatic insulin sensitivityThe n-3 PUFA diet had no effect in the GPR120 knockout(KO) mice On chow diets the GPR120 KO mice showedmoderate insulin resistance with no changes in food intake orbody weight On high-fat diet (HFD) the GPR120 KO micegained more weight than wild-type controls [3] In humansGPR120 expression in adipose tissue is significantly higher inobese individuals than in lean controls [80] Ichimura andcolleagues compared sequences of GPR120 exons in obesepopulations and discovered a deleterious nonsynonymousmutation (R270H) [80] Their population study showed thatthe GPR120R270H variant correlated with obesity Furtherinvestigation in vitro demonstrated that the GPR120R270H


variant was unable to respond to long-chain fatty acidstimulation This inactive mutant of GPR120 may contributeto its significant association with obesity [80]

Toll-like receptors (TLRs) are transmembrane glycopro-tein receptors that are important regulators of the innateimmune system TLRs are considered a link between innate(nonspecific) and adaptive (specific) immunity and con-tribute to the immune systemrsquos capacity to efficiently combatpathogens [82] TLR expression is increased in tumorsincluding breast colorectal melanoma lung prostate pan-creatic and liver cancer [83] Activation of TLRs triggersa signaling cascade producing inflammatory cytokines thatrecruit components of the adaptive immune system to kill thepathogen [84] Among the family of TLRs TLR4 and TLR9have been reported to be associated with prostate cancer[85ndash87] Panigrahy et al reported that saturated fatty acidsactivated and DHA inhibited TLR2- and TLR4-mediatedproinflammatory activity in a cell culture system [88] Satu-rated fatty acidsmay stimulate the TLR4 signaling pathway totrigger the production of proinflammatory mediators whichmay contribute to neuronal death [89]

PPARs (PPAR120572 PPAR120573120575 and PPAR120574) are a super-family of ligand-activated transcription factors and nuclearhormone receptors The syndecan family of cell surfaceproteoglycans share a structure of small conserved cyto-plasmic and transmembrane domains and larger distinctectodomain They are implicated in a variety of physiologicandpathologic processes such as nutrientmetabolism energyhomeostasis inflammation and cancer Growing evidencehas demonstrated that PPAR120574 serves as a tumor suppressorin cancer (see review of Robbins and Nie 2012) [90] n-3PUFA can induce apoptosis in human prostate cancer cellsby activating the nuclear receptor PPAR120574 and upregulatingthe PPAR120574 target gene syndecan-1 (SDC-1) [49 91] It hasbeen suggested that n-3 PUFA induces cell apoptosis inprostate cancer via a mechanism of LOX15-mediated SDC-1-dependent suppression of PDPK1AKTBAD phosphory-lation [49 91] SDC-1 upregulation by DHA has also beendemonstrated in human breast cancer cells [19 92ndash94] and inn-3 PUFA-enriched mammary glands and liver of fat-1 mice[95]

SDC-1 plays several important cellular functions It reg-ulates many steps of leukocyte recruitment in noninfectiousinflammatory diseases attenuates inflammation by modu-lating heparin sulfate-binding proinflammatory factors andplays a key role in the normal remodeling of injured cardiactissues [96] Loss of cell surface SDC-1 seen in manycarcinomas such as skin cancer and colorectal adenocar-cinomas favors acquisition of the metastatic phenotype incancer cells [97] There is very limited information aboutSDC-1 expression in prostate cancer Some studies reportedan inverse relationship between SDC-1 and Gleason score[98 99] but a tissue microarray analysis in another studyshowed an increase in SDC-1 with tumor progression [100]Our own studies have shown reduced expression of SDC-1 in prostate cancer cell lines compared to normal prostateepithelial cells and lower expression in androgen-dependentLNCaP cells compared to androgen-independent PC3 andDU145 cells [49] In a mouse prostate cancer model the

reduction in tumor growth as a result of dietary n-3 PUFAis accompanied by an increase in the expression of secretedSDC-1 [49 101]

Several other receptors have been suggested as targets forn-3 PUFA action Turk et al reported that DHA can inducethe alteration in both the lateral and subcellular localizationof EGFR and suppress EGFR signaling which suggestsimplications for the molecular basis of cancer prevention byDHA [44 102] It is also reported that DHA can increaseCD95 (Fas ligand death receptor) cell surface expressionand may mediate CD95-induced apoptosis [103] For moreinformation about PUFA receptor interaction please refer toa review by Lee et al [104]

44 Other Mechanisms Nuclear factor erythroid-2-relatedfactor 2 (Nrf2) is a basic leucine zipper transcription factorNrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1) under basal conditions Whenthe cell is challenged by oxidative stress Nrf2 is released fromKeap1 inhibition translocates to the nucleus forms a com-plex with other factors and activates transcription of genescontaining an antioxidant response element (ARE) in theirpromoter regionNrf2 has been reported to play an importantrole in lung injury reversal human endothelial cell survivalneuroinflammation hyperoxia lung damage from cigarettesmoking and impaired function ofmacrophages [105] Otherstudies suggest that Nrf2 suppresses inflammation by inhibit-ing NF120581B activation through regulation of redox balancecalcium signaling and PPARs [106] Various human cancerssuch as lung cancer frequently exhibit increased levels ofNrf2 [107] Downregulation of nuclear Nrf2 gene expressionby RNAi-mediated silencing in nonsmall cell lung cancerinhibits tumor growth and increases efficacy of chemotherapy[108] Cancer cells are suspected to hijack the Keap1-Nrf2system as a means to acquire malignant properties Indeedthe prognosis of patients carrying Nrf2-positve cancers ispoor [105] Oxidized n-3 fatty acids can react directly with thenegative regulator of Nrf2 Keap1 by dissociating them andinducing Nrf2-directed gene expression [109] For examplen-3 PUFAmediators can activate Nrf2 in vascular endothelialcells to prevent oxidative stress-induced cytotoxicity [110]DHA and EPA can induce Nrf2 expression and suppresslipopolysaccharide-(LPS-) induced inflammation [111] Evi-dence of Nrf2-mediated response modulated by n-3 PUFAin prostate cancer came from a randomized clinical trialEighty-four men with low-risk prostate cancer were stratifiedbased on self-reported dietary consumption of fish oilExploratory pathway analyses of rank-ordered genes revealedthe modulation of Nrf2 or Nrf2-mediated oxidative responseafter 3 months of fish oil supplementation (119875 = 001) [112]

Calcium (Ca2+) signaling is a ubiquitous mechanism inthe control of cell function The transient receptor potentialchannels (TRP channels) are 6 transmembrane-spanningproteins with both amino and carboxyl tails located onthe intracellular side of the membrane Ca2+ flux throughTRP channels located in the plasma membrane and in themembranes of excitable intracellular organelles can promotechanges in intracellular free Ca2+ concentrations and the


Table 1 Mechanism of n-3 PUFA action

Target Mechanism of action ReferencesMembrane PIPs Suppress PI3KAKTBAD survival pathway [17 40]SDC-1 Suppress PI3KAKTBAD and AKTNF120581B survival pathway [49]Unknown Suppress AKTNF120581B or PI3KAKTp38 MAPK pathway [50 51]GPR40 Mediate insulin secretion cell proliferation [75ndash77]GPR120 Anti-inflammation [3 80]TLRs Suppress the production of proinflammatory mediators [88 89]PPARg Induce cell apoptosis [90]Nrf2 Suppress inflammation reduce oxidative stress [106 109 110]Calcium signaling Inhibit cell proliferation [114]COXs Promote inflammation [52]LOXs Promote inflammation [53]E-resolvins Resolve inflammation [62]D-resolvins Resolve inflammation [62]

membrane potential which can modulate the driving forcefor other ions and Ca2+ itself [113] Evidence suggests thatTRP channel function can be modulated both directly andindirectly by n-3 fatty acids [114] It was demonstrated thatDHAandEPAat physiological concentrations have the abilityto evoke small currents which seems to be dependent onthe previous sensitization of the channel by protein kinaseC (PKC) Whether these effects are due to the action ofthese PUFAs on the agonist binding site or are due toconformational changes caused by TRP protein interactionswith the lipid bilayer requires further investigation [115]Recent findings also indicate that TRP channel functioncan be modulated by D and E resolvins Resolvin bindingon GPCRs seems to be part of the mechanism underlyingthe resolvin-mediated regulation of TRP channel function[116] DHA significantly reduces oxidative stress-inducedendothelial cell Ca2+ influx This effect might be associatedat least in part with altered lipid composition in membranecaveolar rafts [117] Ca2+ has been shown to be essentialfor increased cell proliferation in prostate cells [118] Sunet al observed significantly higher Ca2+ influx in prostatecancer cells They reported that high ratio of Ca2+Mg2+facilitated Ca2+ influx and led to a significant increase incell proliferation of prostate cancer [119] Thus one couldspeculate that n-3 PUFA might indirectly modulate prostatecancer growth by directly modulating Ca2+ influx

5 Conclusions

Cancer incidence andmortality are high in theWesternworldand a high n-6 to n-3 PUFA ratio in the Western diet maybe a contributing factor There is much evidence to suggestthat n-3 PUFA has antiproliferative effects in cancer celllines animal models and humans Direct effects on cancercells and indirect effects on the host immune system (anti-inflammation) likely contribute to the inhibitory effect of n-3fatty acids on tumor growth however further investigationis warranted n-3 PUFA may also regulate other complex

metabolic processes including 120573-oxidation lipid releasefrom glycerophospholipids cellular signaling of membranebound proteins eicosanoid synthesis and direct activationof nuclear receptors and gene transcription all of whichmay influence the development and progression of prostatecancer Overall there seems to be an exceptionally broadpotential for the mechanisms mediating cancer preventionby n-3 PUFA (summarized in Table 1) We expect that newresearch in lipidomics and metabolomics will provide newtechniques and approaches to answering the many questionsthat remain regarding the mechanisms underlying the healthbenefits of n-3 PUFA

Abbreviations

PUFA Polyunsaturated fatty acidEPA Eicosapentaenoic acid (205 n-3)DHA Docosahexaenoic acid (226 n-3)LA Linoleic acid (182 n-6)AA Arachidonic acid (204 n-6)ALA Alpha linolenic acid (183 n-3)FADS Fatty acid desaturaseGLA Gamma-linolenic acid (183 n-6)DGLA Dihomo-gamma-linolenic acid (203 n-6)KAR 3-Ketoacyl-CoA reductaseHACD 3-Hydroxyacyl-CoA dehydrataseTECR Trans-23-enoyl-CoA reductaseDPA Docosapentaenoic acid (225 n-3)PC PhosphatidylcholinePS PhosphatidylserinePE PhosphatidylethanolaminePI PhosphatidylinositolSA Stearic acid (180)GPCR G Protein-coupled receptorEGFR Epidermal growth factor receptorAKT Serinethreonine protein kinase (protein kinase B)PI3K Phosphatidylinositol-3-kinasePIP3 PI-345-trisphosphate


PH Pleckstrin homologyPDPK1 Phosphoinositide-dependent kinase-1SDC-1 Syndecan-1COX CyclooxygenaseLOX LipoxygenaseRvE1 E-Resolvin1RvD1 D-Resolvin1TLR Toll-like receptorPPAR Peroxisome proliferator-activated receptorMCFA Medium-chain fatty acidBMDC Bone marrow-derived CD11C+ macrophageKO KnockoutHFD High-fat dietNrf2 Nuclear factor erythroid-2-related factor 2Keap1 Kelch-like ECH-associated protein 1ARE Antioxidant response elementLPS LipopolysaccharidePKC Protein kinase C

References

[1] H O Bang J Dyerberg and A B Nielsen ldquoPlasma lipid andlipoprotein pattern in Greenlandic West-coast Eskimosrdquo TheLancet vol 1 no 7710 pp 1143ndash1145 1971

[2] J Dyerberg HO Bang andNHjorne ldquoFatty acid compositionof the plasma lipids in Greenland Eskimosrdquo The AmericanJournal of Clinical Nutrition vol 28 no 9 pp 958ndash966 1975

[3] D Y Oh S Talukdar E J Bae et al ldquoGPR120 is an Omega-3 fatty acid receptor mediating potent anti-inflammatory andinsulin-sensitizing effectsrdquo Cell vol 142 no 5 pp 687ndash6982010

[4] A Ariel and C N Serhan ldquoResolvins and protectins inthe termination program of acute inflammationrdquo Trends inImmunology vol 28 no 4 pp 176ndash183 2007

[5] C A Daley A Abbott P S Doyle G A Nader and S LarsonldquoA review of fatty acid profiles and antioxidant content in grass-fed and grain-fed beefrdquoNutrition Journal vol 9 no 1 article 102010

[6] J T Bernert Jr and H Sprecher ldquoStudies to determine the rolerates of chain elongation and desaturation play in regulatingthe unsaturated fatty acid composition of rat liver lipidsrdquoBiochimica et Biophysica Acta vol 398 no 3 pp 354ndash363 1975

[7] I M Berquin I J Edwards S J Kridel and Y Q ChenldquoPolyunsaturated fatty acid metabolism in prostate cancerrdquoCancer and Metastasis Reviews vol 30 no 3-4 pp 295ndash3092011

[8] J V Swinnen K Brusselmans and G Verhoeven ldquoIncreasedlipogenesis in cancer cells new players novel targetsrdquo CurrentOpinion in Clinical Nutrition and Metabolic Care vol 9 no 4pp 358ndash365 2006

[9] F P Kuhajda ldquoFatty acid synthase and cancer new applicationof an old pathwayrdquo Cancer Research vol 66 no 12 pp 5977ndash5980 2006

[10] J A Menendez and R Lupu ldquoFatty acid synthase and thelipogenic phenotype in cancer pathogenesisrdquo Nature ReviewsCancer vol 7 no 10 pp 763ndash777 2007

[11] J Suburu and Y Q Chen ldquoLipids and prostate cancerrdquoProstaglandins andOther LipidMediators vol 98 pp 1ndash10 2012

[12] G C Burdge and P C Calder ldquoConversion of 120572-linolenic acidto longer-chain polyunsaturated fatty acids in human adultsrdquo

Reproduction Nutrition Development vol 45 no 5 pp 581ndash5972005

[13] C M Williams and G Burdge ldquoLong-chain n-3 PUFA plant vmarine sourcesrdquo Proceedings of the Nutrition Society vol 65 no1 pp 42ndash50 2006

[14] R J Pawlosky J RHibbeln J ANovotny andN Salem ldquoPhysi-ological compartmental analysis of 120572-linolenic acidmetabolismin adult humansrdquo Journal of Lipid Research vol 42 no 8 pp1257ndash1265 2001

[15] A P Simopoulos ldquoEvolutionary aspects of omega-3 fatty acidsin the food supplyrdquo Prostaglandins Leukotrienes and EssentialFatty Acids vol 60 no 5-6 pp 421ndash429 1999

[16] A P Simopoulos ldquoThe importance of the ratio of omega-6omega-3 essential fatty acidsrdquo Biomedicine and Pharma-cotherapy vol 56 no 8 pp 365ndash379 2002

[17] I M Berquin Y Min R Wu et al ldquoModulation of prostatecancer genetic risk by omega-3 and omega-6 fatty acidsrdquo Journalof Clinical Investigation vol 117 no 7 pp 1866ndash1875 2007

[18] G Calviello F Resci S Serini et al ldquoDocosahexaenoicacid induces proteasome-dependent degradation of 120573-catenindown-regulation of survivin and apoptosis in human colorectalcancer cells not expressing COX-2rdquo Carcinogenesis vol 28 no6 pp 1202ndash1209 2007

[19] H Sun I M Berquin R T Owens J T OrsquoFlaherty andI J Edwards ldquoPeroxisome proliferator-activated receptor 120574-mediated up-regulation of syndecan-1 by n-3 fatty acids pro-motes apoptosis of human breast cancer cellsrdquo Cancer Researchvol 68 no 8 pp 2912ndash2919 2008

[20] I M Berquin I J Edwards and Y Q Chen ldquoMulti-targetedtherapy of cancer by omega-3 fatty acidsrdquo Cancer Letters vol269 no 2 pp 363ndash377 2008

[21] Y Q Chen I J Edwards S J Kridel T Thornburg and IM Berquin ldquoDietary fat-gene interactions in cancerrdquo CancerMetastasis Reviews vol 26 pp 535ndash551 2007

[22] S Wang J Wu J Suburu Z Gu J Cai et al ldquoEffect of dietarypolyunsaturated fatty acids on castration-resistant Pten-nullprostate cancerrdquo Carcinogenesis vol 33 pp 404ndash412 2012

[23] K K Carroll ldquoDietary fat and cancer specific action or caloriceffectrdquo Journal of Nutrition vol 116 no 6 pp 1130ndash1132 1986

[24] M Gerber ldquoOmega-3 fatty acids and cancers a systematicupdate review of epidemiological studiesrdquo British Journal ofNutrition vol 107 Supplement 2 pp 228ndash239 2012

[25] PD Terry T E Rohan andAWolk ldquoIntakes of fish andmarinefatty acids and the risks of cancers of the breast and prostate andof other hormone-related cancers a review of the epidemiologicevidencerdquoTheAmerican Journal of Clinical Nutrition vol 77 no3 pp 532ndash543 2003

[26] C H MacLean S J Newberry W A Mojica et al ldquoEffects ofomega-3 fatty acids on cancer risk a systematic reviewrdquo Journalof the AmericanMedical Association vol 295 no 4 pp 403ndash4152006

[27] Y Q Chen I M Berquin L W Daniel et al ldquoOmega-3fatty acids and cancer riskrdquo Journal of the American MedicalAssociation vol 296 no 3 pp 278ndash282 2006

[28] M C Schumacher B Laven F Petersson et al ldquoA comparativestudy of tissue 120596-6 and 120596-3 polyunsaturated fatty acids (PUFA)in benign andmalignant pathologic stage pT2a radical prostate-ctomy specimensrdquoUrologic Oncology vol 31 no 3 pp 318ndash3242013

[29] CDWilliams BMWhitley CHoyoD J Grant J D Iraggi etal ldquoA high ratio of dietary n-6n-3 polyunsaturated fatty acids


is associated with increased risk of prostate cancerrdquo NutritionResearch vol 31 no 1 pp 1ndash8 2011

[30] M D Brown C Hart E Gazi P Gardner N Lockyer and NClarke ldquoInfluence of omega-6 PUFA arachidonic acid and bonemarrow adipocytes on metastatic spread from prostate cancerrdquoBritish Journal of Cancer vol 102 no 2 pp 403ndash413 2010

[31] C R Ritch R L Wan L B Stephens et al ldquoDietary fattyacids correlate with prostate cancer biopsy grade and volumein Jamaican menrdquo Journal of Urology vol 177 no 1 pp 97ndash1012007

[32] N Sawada M Inoue M Iwasaki S Sasazuki T Shimazu etal ldquoConsumption of n-3 fatty acids and fish reduces risk ofhepatocellular carcinomardquo Gastroenterology vol 142 pp 1468ndash1475 2012

[33] S Sasazuki M Inoue M Iwasaki et al ldquoIntake of n-3 andn-6 polyunsaturated fatty acids and development of colorectalcancer by subsite JapanPublicHealthCenter-based prospectivestudyrdquo International Journal of Cancer vol 129 no 7 pp 1718ndash1729 2011

[34] J E Chavarro M J Stampfer H Li H Campos T Kurthand J Ma ldquoA prospective study of polyunsaturated fatty acidlevels in blood and prostate cancer riskrdquo Cancer EpidemiologyBiomarkers and Prevention vol 16 no 7 pp 1364ndash1370 2007

[35] K M Szymanski D C Wheeler and L A Mucci ldquoFishconsumption and prostate cancer risk a review and meta-analysisrdquoTheAmerican Journal of Clinical Nutrition vol 92 no5 pp 1223ndash1233 2010

[36] N Kobayashi R J Barnard S M Henning et al ldquoEffect ofaltering dietary 120596-6120596-3 fatty acid ratios on prostate cancermembrane composition cyclooxygenase-2 and prostaglandinE 2rdquo Clinical Cancer Research vol 12 no 15 pp 4662ndash46702006

[37] M D Brown C A Hart E Gazi S Bagley and N W ClarkeldquoPromotion of prostatic metastatic migration towards humanbone marrow stoma by Omega 6 and its inhibition by Omega3 PUFAsrdquo British Journal of Cancer vol 94 no 6 pp 842ndash8532006

[38] M C Chabot J D Schmitt B C Bullock and R L WykleldquoReacylation of platelet activating factor with eicosapentaenoicacid in fish-oil-enriched monkey neutrophilsrdquo Biochimica etBiophysica Acta vol 922 no 2 pp 214ndash220 1987

[39] M Picq P Chen M Perez M Michaud E Vericel et al ldquoDHAmetabolism targeting the brain and lipoxygenationrdquoMolecularNeurobiology vol 42 pp 48ndash51 2010

[40] Z Gu J Wu S Wang et al ldquoPolyunsaturated fatty acids affectthe localization and signaling of PIP3AKT in prostate cancercellsrdquo Carcinogenesis 2013

[41] S R Wassall and W Stillwell ldquoDocosahexaenoic acid domainsthe ultimate non-raft membrane domainrdquo Chemistry andPhysics of Lipids vol 153 no 1 pp 57ndash63 2008

[42] N V Eldho S E Feller S Tristram-Nagle I V Polozov andK Gawrisch ldquoPolyunsaturated docosahexaenoic vs docosapen-taenoic acid - Differences in lipid matrix properties from theloss of one double bondrdquo Journal of the American ChemicalSociety vol 125 no 21 pp 6409ndash6421 2003

[43] D C Mitchell S L Niu and B J Litman ldquoQuantifying thedifferential effects of DHA andDPAon the early events in visualsignal transductionrdquo Chemistry and Physics of Lipids vol 165pp 393ndash400 2012

[44] H F Turk R Barhoumi andR S Chapkin ldquoAlteration of EGFRspatiotemporal dynamics suppresses signal transductionrdquo PLoSOne vol 7 no 6 Article ID e39682 2012

[45] S R Datta H Dudek T Xu et al ldquoAkt phosphorylation of BADcouples survival signals to the cell- intrinsic death machineryrdquoCell vol 91 no 2 pp 231ndash241 1997

[46] T Maehama and J E Dixon ldquoThe tumor suppressorPTENMMAC1 dephosphorylates the lipid second messengerphosphatidylinositol 345-trisphosphaterdquo Journal of BiologicalChemistry vol 273 no 22 pp 13375ndash13378 1998

[47] J A Engelman J Luo and L C Cantley ldquoThe evolutionof phosphatidylinositol 3-kinases as regulators of growth andmetabolismrdquoNature Reviews Genetics vol 7 no 8 pp 606ndash6192006

[48] T F Franke ldquoPI3KAkt getting it right mattersrdquo Oncogene vol27 no 50 pp 6473ndash6488 2008

[49] Y Hu H Sun R T Owens et al ldquoSyndecan-1-dependentsuppression of PDK1AktBad signaling by docosahexaenoicacid induces apoptosis in prostate cancerrdquoNeoplasia vol 12 no10 pp 826ndash836 2010

[50] P D Schley H B Jijon L E Robinson and C J FieldldquoMechanisms of omega-3 fatty acid-induced growth inhibitionin MDA-MB-231 human breast cancer cellsrdquo Breast CancerResearch and Treatment vol 92 no 2 pp 187ndash195 2005

[51] J L D Toit-Kohn L Louw and A M Engelbrecht ldquoDocosa-hexaenoic acid induces apoptosis in colorectal carcinoma cellsbymodulating the PI3 kinase andp38MAPKpathwaysrdquo Journalof Nutritional Biochemistry vol 20 no 2 pp 106ndash114 2009

[52] R N DuBois S B Abramson L Crofford et al ldquoCyclooxyge-nase in biology and diseaserdquo FASEB Journal vol 12 no 12 pp1063ndash1073 1998

[53] G P Pidgeon J Lysaght S Krishnamoorthy et al ldquoLipoxy-genase metabolism roles in tumor progression and survivalrdquoCancer and Metastasis Reviews vol 26 no 3-4 pp 503ndash5242007

[54] Y N Ye W K K Wu V Y Shin I C Bruce B C YWong and C H Cho ldquoDual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarettesmokerdquo Carcinogenesis vol 26 no 4 pp 827ndash834 2005

[55] B K Sharma P Pilania and P Singh ldquoModeling ofcyclooxygenase-2 and 5-lipooxygenase inhibitory activityof apoptosis-inducing agents potentially useful in prostatecancer chemotherapy derivatives of diarylpyrazolerdquo Journal ofEnzyme Inhibition and Medicinal Chemistry vol 24 no 2 pp607ndash615 2009

[56] M Diederich C Sobolewski C Cerella M Dicato and LGhibelli ldquoThe role of cyclooxygenase-2 in cell proliferation andcell death in human malignanciesrdquo International Journal of CellBiology Article ID 215158 2010

[57] M T Wang K V Honn and D Nie ldquoCyclooxygenasesprostanoids and tumor progressionrdquo Cancer and MetastasisReviews vol 26 no 3-4 pp 525ndash534 2007

[58] D G Menter R L Schilsky and R N DuBoisldquoCyclooxygenase-2 and cancer treatment understandingthe risk should be worth the rewardrdquo Clinical Cancer Researchvol 16 no 5 pp 1384ndash1390 2010

[59] A C Reese V Fradet and J S Witte ldquo120596-3 Fatty acids geneticvariants in COX-2 and prostate cancerrdquo Journal of Nutrigeneticsand Nutrigenomics vol 2 no 3 pp 149ndash158 2009

[60] H O Bang J Dyerberg and N Hjorne ldquoThe composition offood consumed by Greenland Eskimosrdquo Acta Medica Scandi-navica vol 200 no 1-2 pp 69ndash73 1976

[61] J Dyerberg H O Bang E Stoffersen S Moncada and J RVane ldquoEicosapentaenoic acid and prevention of thrombosis andatherosclerosisrdquoThe Lancet vol 2 no 8081 pp 117ndash119 1978


[62] C N Serhan C B Clish J Brannon S P Colgan N Chiangand K Gronert ldquoNovel functional sets of lipid-derived medi-ators with antiinflammatory actions generated from omega-3fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatorydrugs and transcellular processingrdquo Journal of ExperimentalMedicine vol 192 no 8 pp 1197ndash1204 2000

[63] H Hasturk A Kantarci T Ohira et al ldquoRvE1 protects fromlocal inflammation and osteoclast-mediated bone destructionin periodontitisrdquo FASEB Journal vol 20 no 2 pp 401ndash4032006

[64] K M Connor J P Sangiovanni C Lofqvist et al ldquoIncreaseddietary intake of120596-3-polyunsaturated fatty acids reduces patho-logical retinal angiogenesisrdquo Nature Medicine vol 13 no 7 pp868ndash873 2007

[65] S Ogawa D Urabe Y Yokokura H Arai M Arita and MInoue ldquoTotal synthesis and bioactivity of resolvin E2rdquo OrganicLetters vol 11 no 16 pp 3602ndash3605 2009

[66] K H Weylandt C Y Chiu B Gomolka S F Waechter and BWiedenmann ldquoOmega-3 fatty acids and their lipid mediatorstowards an understanding of resolvin and protectin formationrdquoProstaglandins and Other Lipid Mediators vol 97 pp 73ndash822012

[67] Y P Sun S F Oh J Uddin et al ldquoResolvin D1 and itsaspirin-triggered 17R epimer stereochemical assignments anti-inflammatory properties and enzymatic inactivationrdquo Journalof Biological Chemistry vol 282 no 13 pp 9323ndash9334 2007

[68] C K Park Z Z Xu T Liu N Lu C N Serhan et al ldquoResolvinD2 is a potent endogenous inhibitor for transient receptorpotential subtype V1A1 inflammatory pain and spinal cordsynaptic plasticity in mice distinct roles of resolvin D1 D2 andE1rdquo Journal of Neuroscience vol 31 pp 18433ndash18438 2011

[69] Y Zhao F Calon C Julien et al ldquoDocosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival viasecretase- and PPAR120574-mediated mechanisms in Alzheimerrsquosdisease modelsrdquo PLoS ONE vol 6 no 1 Article ID e15816 2011

[70] H Tazoe Y Otomo I Kaji R Tanaka S I Karaki and AKuwahara ldquoRoles of short-chain fatty acids receptors GPR41and GPR43 on colonic functionsrdquo Journal of Physiology andPharmacology vol 59 supplement 2 pp 251ndash262 2008

[71] J Wang X Wu N Simonavicius H Tian and L LingldquoMedium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84rdquo Journal of Biological Chemistry vol281 no 45 pp 34457ndash34464 2006

[72] Y Itoh Y Kawamata M Harada et al ldquoFree fatty acids regulateinsulin secretion from pancreatic 120573 cells through GPR40rdquoNature vol 422 no 6928 pp 173ndash176 2003

[73] A Hirasawa K Tsumaya T Awaji et al ldquoFree fatty acidsregulate gut incretin glucagon-like peptide-1 secretion throughGPR120rdquo Nature Medicine vol 11 no 1 pp 90ndash94 2005

[74] M Suzuki S Takaishi M Nagasaki Y Onozawa I Iino etal ldquoMedium-chain fatty acid-sensing receptor GPR84 is aproinflammatory receptorrdquo Journal of Biological Chemistry vol288 pp 10684ndash10691 2013

[75] C P Briscoe M Tadayyon J L Andrews et al ldquoThe orphanG protein-coupled receptor GPR40 is activated by medium andlong chain fatty acidsrdquo Journal of Biological Chemistry vol 278no 13 pp 11303ndash11311 2003

[76] S Hardy G G St-Onge E Joly Y Langelier and M PrentkildquoOleate promotes the proliferation of breast cancer cells viathe G protein-coupled receptor GPR40rdquo Journal of BiologicalChemistry vol 280 no 14 pp 13285ndash13291 2005

[77] T Alquier M L Peyot M G Latour et al ldquoDeletion ofGPR40 impairs glucose-induced insulin secretion in vivo inmice without affecting intracellular fuel metabolism in isletsrdquoDiabetes vol 58 no 11 pp 2607ndash2615 2009

[78] K Nakamoto T Nishinaka K Matsumoto F Kasuya MMankura et al ldquoInvolvement of the long-chain fatty acidreceptor GPR40 as a novel pain regulatory systemrdquo BrainResearch vol 1432 pp 74ndash83 2012

[79] D Ma M Zhang C P Larsen et al ldquoDHA promotes theneuronal differentiation of rat neural stem cells transfected withGPR40 generdquo Brain Research vol 1330 pp 1ndash8 2010

[80] A Ichimura A Hirasawa O Poulain-Godefroy A BonnefondT Hara et al ldquoDysfunction of lipid sensor GPR120 leads toobesity in both mouse and humanrdquo Nature vol 483 pp 350ndash354 2012

[81] D Y Oh and J M Olefsky ldquoOmega 3 fatty acids and GPR120rdquoCell Metabolism vol 15 pp 564ndash565 2012

[82] T Kawai and S Akira ldquoTLR signalingrdquo Cell Death and Differ-entiation vol 13 no 5 pp 816ndash825 2006

[83] L A Ridnour R Y Cheng C H Switzer J L Heinecke SAmbs et al ldquoMolecular Pathways toll-like receptors in thetumor microenvironment poor prognosis or new therapeuticopportunityrdquo Clinical Cancer Research vol 19 no 6 pp 1340ndash1346 2012

[84] J Krishnan G Lee and S Choi ldquoDrugs targeting toll-likereceptorsrdquo Archives of Pharmacal Research vol 32 no 11 pp1485ndash1502 2009

[85] A Paone D Starace R Galli et al ldquoToll-like receptor 3 triggersapoptosis of human prostate cancer cells through a PKC-120572-dependent mechanismrdquo Carcinogenesis vol 29 no 7 pp 1334ndash1342 2008

[86] S L Zheng K Augustsson-Balter B Chang et al ldquoSequencevariants of toll-like receptor 4 are associated with prostatecancer risk results from the cancer prostate in Sweden studyrdquoCancer Research vol 64 no 8 pp 2918ndash2922 2004

[87] M R Vaisanen T Vaisanen A Jukkola-Vuorinen et alldquoExpression of toll-like receptor-9 is increased in poorly differ-entiated prostate tumorsrdquo Prostate vol 70 no 8 pp 817ndash8242010

[88] D Panigrahy A Kaipainen E R Greene and S HuangldquoCytochrome P450-derived eicosanoids the neglected pathwayin cancerrdquoCancerMetastasis Reviews vol 29 no 4 pp 723ndash7352010

[89] Z Wang D Liu F Wang S Liu S Zhao et al ldquoSaturatedfatty acids activatemicroglia via Toll-like receptor 4NF-kappaBsignallingrdquo British Journal of Nutrition vol 107 pp 229ndash2412012

[90] G T Robbins and D Nie ldquoPPAR gamma bioactive lipids andcancer progressionrdquo Frontiers in Bioscience vol 17 pp 1816ndash1834 2012

[91] H JMurff X O ShuH Li et al ldquoDietary polyunsaturated fattyacids and breast cancer risk in Chinese women a prospectivecohort studyrdquo International Journal of Cancer vol 128 no 6 pp1434ndash1441 2011

[92] H Sun Y Hu Z Gu R T Owens Y Q Chen et al ldquoOmega-3 fatty acids induce apoptosis in human breast cancer cells andmouse mammary tissue through syndecan-1 inhibition of theMEK-Erk pathwayrdquo Carcinogenesis vol 32 pp 1518ndash1524 2011

[93] I J Edwards I M Berquin H Sun et al ldquoDifferential effectsof delivery of omega-3 fatty acids to human cancer cells by low-density lipoproteins versus albuminrdquo Clinical Cancer Researchvol 10 no 24 pp 8275ndash8283 2004


[94] H Sun I M Berquin and I J Edwards ldquoOmega-3 polyunsatu-rated fatty acids regulate syndecan-1 expression in humanbreastcancer cellsrdquo Cancer Research vol 65 no 10 pp 4442ndash44472005

[95] H Sun Y Hu Z Gu et al ldquoEndogenous synthesis of n-3polyunsaturated fatty acids in Fat-1 mice is associated withincreased mammary gland and liver Syndecan-1rdquo PLoS ONEvol 6 no 5 Article ID e20502 2011

[96] Y H Teng R S Aquino and P W Park ldquoMolecular functionsof syndecan-1 in diseaserdquoMatrix Biology vol 31 pp 3ndash16 2012

[97] T Ishikawa and R H Kramer ldquoSdc1 negatively modulates car-cinoma cell motility and invasionrdquo Experimental Cell Researchvol 316 no 6 pp 951ndash965 2010

[98] J Kiviniemi M Kallajoki I Kujala et al ldquoAltered expression ofsyndecan-1 in prostate cancerrdquoAPMIS vol 112 no 2 pp 89ndash972004

[99] D Chen B Adenekan L Chen et al ldquoSyndecan-1 expressionin locally invasive and metastatic prostate cancerrdquo Urology vol63 no 2 pp 402ndash407 2004

[100] T Zellweger C Ninck M Mirlacher et al ldquoTissue microarrayanalysis reveals prognostic significance of syndecan-I expres-sion in prostate cancerrdquo Prostate vol 55 no 1 pp 20ndash29 2003

[101] I J Edwards H Sun YHu et al ldquoIn vivo and in vitro regulationof syndecan 1 in prostate cells by n-3 polyunsaturated fattyacidsrdquo Journal of Biological Chemistry vol 283 no 26 pp18441ndash18449 2008

[102] P A Corsetto G Montorfano S Zava I E Jovenitti ACremona and A M Rizzo ldquoEffects of n-3 PUFAs on breastcancer cells through their incorporation in plasma membranerdquoLipids in Health and Disease vol 10 article 73 2011

[103] J B EwaschukMNewell andC J Field ldquoDocosahexanoic acidimproves chemotherapy efficacy by inducing CD95 transloca-tion to lipid rafts in ER(-) breast cancer cellsrdquo Lipids vol 47 pp1019ndash1030 2012

[104] J Y Lee L Zhao and D H Hwang ldquoModulation of pat-tern recognition receptor-mediated inflammation and risk ofchronic diseases by dietary fatty acidsrdquo Nutrition Reviews vol68 no 1 pp 38ndash61 2010

[105] Y Mitsuishi H Motohashi and M Yamamoto ldquoTheKeap1-Nrf2 system in cancers stress response and anabolicmetabolismrdquo Frontiers in Oncology vol 2 article 200 2012

[106] H Wang T O Khor C L L Saw et al ldquoRole of Nrf2 insuppressing LPS-induced inflammation in mouse peritonealmacrophages by polyunsaturated fatty acids docosahexaenoicacid and eicosapentaenoic acidrdquo Molecular Pharmaceutics vol7 no 6 pp 2185ndash2193 2010

[107] P Zhang A Singh S Yegnasubramanian et al ldquoLoss ofkelch-like ECH-associated protein 1 function in prostate cancercells causes chemoresistance and radioresistance and promotestumor growthrdquoMolecular Cancer Therapeutics vol 9 no 2 pp336ndash346 2010

[108] A Singh S Boldin-Adamsky R KThimmulappa et al ldquoRNAi-mediated silencing of nuclear factor erythroid-2-related fac-tor 2 gene expression in non-small cell lung cancer inhibitstumor growth and increases efficacy of chemotherapyrdquo CancerResearch vol 68 no 19 pp 7975ndash7984 2008

[109] L Gao J Wang K R Sekhar et al ldquoNovel n-3 fatty acid oxi-dation products activate Nrf2 by destabilizing the associationbetweenKeap1 andCullin3rdquo Journal of Biological Chemistry vol282 no 4 pp 2529ndash2537 2007

[110] A Ishikado Y Nishio K Morino et al ldquoLow concentrationof 4-hydroxy hexenal increases heme oxygenase-1 expressionthrough activation of Nrf2 and antioxidative activity in vascularendothelial cellsrdquo Biochemical and Biophysical Research Com-munications vol 402 no 1 pp 99ndash104 2010


[112] M J Magbanua R Roy E V Sosa VWeinberg S Federman etal ldquoGene expression and biological pathways in tissue of menwith prostate cancer in a randomized clinical trial of lycopeneand fish oil supplementationrdquo PLoS One vol 6 no 9 Article IDe24004 2011

[113] BMinke ldquoTRP channels and Ca2+ signalingrdquoCell Calcium vol40 no 3 pp 261ndash275 2006

[114] J A Matta R L Miyares and G P Ahern ldquoTRPV1 is anovel target for omega-3 polyunsaturated fatty acidsrdquo Journalof Physiology vol 578 no 2 pp 397ndash411 2007

[115] M Parnas M Peters and B Minke ldquoLinoleic acid inhibits TRPchannels with intrinsic voltage sensitivity implications on themechanism of linoleic acid actionrdquo Channels vol 3 no 3 pp164ndash166 2009

[116] M Leonelli M F Graciano and L R Britto ldquoTRP channelsomega-3 fatty acids and oxidative stress in neurodegenerationfrom the cell membrane to intracellular cross-linksrdquo BrazilianJournal of Medical and Biological Research vol 44 pp 1088ndash1096 2011

[117] S Ye L Tan J Ma Q Shi and J Li ldquoPolyunsaturated docosa-hexaenoic acid suppresses oxidative stress induced endothelialcell calcium influx by altering lipid composition in membranecaveolar raftsrdquo Prostaglandins Leukotrienes and Essential FattyAcids vol 83 no 1 pp 37ndash43 2010

[118] M Flourakis andN Prevarskaya ldquoInsights into Ca2+ homeosta-sis of advanced prostate cancer cellsrdquo Biochimica et BiophysicaActa vol 1793 no 6 pp 1105ndash1109 2009

[119] Y Sun S Selvaraj A Varma S Derry A E Sahmoun et alldquoIncrease in serum Ca2+Mg2+ ratio promotes proliferation ofprostate cancer cells by activating TRPM7 channelsrdquo Journal ofBiological Chemistry vol 288 pp 255ndash263 2013

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


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Zoology


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GenomicsInternational Journal of


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Stem CellsInternational



Enzyme Research



Microbiology


fatty acids family member 5) a reduction reaction mediatedby 3-ketoacyl-CoA reductase (KAR) a dehydration reactioncatalyzed by 3-hydroxyacyl-CoA dehydratase (HACD) anda second reduction reaction catalyzed by trans-23-enoyl-CoA reductase (TECR) Finally DGLA is converted to AAby delta-5 desaturase or fatty acid desaturase 1 (FADS1) [6 7]Interestingly malonyl-CoA which is necessary for fatty acidelongation is derived from the rate-limiting enzyme of thede novo fatty acid synthesis pathway acetyl-CoA carboxylaseFatty acid synthesis is well described as an overactive pathwayin many cancers [8ndash11] and its upregulation may also con-tribute to the elongation of PUFA

In contrast to AA the efficiency of ALA conversion toDHA appears to be very low below 5 in humans Mostingested ALA is subject to beta-oxidation to provide energyand only a small fraction is converted to EPA [12 13] Itwas estimated that as low as 02 of ALA is converted toEPA 64 of EPA to docosapentaenoic acid (DPA 225 n-3)and 37 of DPA to DHA [14] Thus the overall amountof DPA and DHA converted from ALA is about 013and 005 of the starting ALA respectively These findingssuggest that any contributions from the fatty acid synthesispathway toward PUFA metabolism most likely favor n-6rather than n-3 PUFA elongation It is also very likely thatsynthesis of the longer n-3 fatty acids from ALA within thebody is competitively hindered by the n-6 analogues It hasbeen reported that the n-3 conversion efficiency is greater inwomen possibly because of the importance of meeting theDHA demands of the fetus and neonate [14]

3 PUFA and Cancer

Total fat intake and the ratio of n-6 to n-3 PUFA in theWestern diet have increased significantly since the IndustrialRevolution [15 16] Increased fat consumption has been asso-ciated with the development of specific types of cancer suchas breast colon and pancreatic and prostate cancers with thenotable exception of n-3 PUFA which show protective effectsagainst colon breast and prostate cancers in a number ofexperimental systems [17ndash23] Epidemiological studies aboutthe association of dietary fat and cancer suggests a protectiveeffect of n-3 PUFA and a promoting effect of n-6 PUFA oncancer Most clinical data regarding the effects of dietary faton cancers are observational [24] and the results of suchstudies are mixed as many fail to demonstrate a significantassociation between n-3 PUFA and reduced prostate cancerrisk or tumor growth [20 25ndash27]

The Western diet contains disproportionally highamounts of n-6 PUFA and low amounts of n-3 PUFAdenoted as a high n-6 to n-3 PUFA ratio Most data regardingthe effects of high dietary n-6 PUFA are positively associatedwith prostate cancer incidence [28ndash30] In a study ofJamaican men undergoing prostate biopsy for elevated PSAlevels a positive correlation was observed between n-6 fattyacid LA and Gleason score and n-6 (LA) to n-3 (DHA)ratio in erythrocyte membranes and prostate tumor volume[31] By comparing PUFA content from malignant andbenign prostatic tissues from the same prostate specimens

a Swedish research group found that n-6 PUFA and n-6PUFA precursors were significantly higher in malignanttissues This finding further demonstrates that n-6 dietaryfat is associated with prostate carcinogenesis [28] In race-specific analyses based on a case-control study comprising79 prostate cancer cases and 187 controls Williams andcolleagues found that a high ratio of n-6 to n-3 fatty acidsmay increase the overall risk of prostate cancer among whitemen and possibly increase the risk of high-grade prostatecancer among all men [29]

At the same time epidemiological literature on theassociation of n-3 PUFA and cancer including correlationalstudies and migrational studies suggest a protective roleplayed by n-3 PUFA In a recent population-based prospec-tive cohort study of 90296 Japanese subjects Sawada et alreported that consumption of n-3-rich fish or n-3 PUFAparticularly EPA DPA and DHA appears to protect againstthe development of hepatocellular carcinoma (HCC) [32] Inanother population-based prospective study in Japan therewas an inverse relationship between marine n-3 PUFA intakeand the risk of colorectal cancer but this association wasonly statistically significant in the proximal site of the largebowel [33] Chavarro et al performed a nested case-controlstudy by analyzing blood samples of 14916 healthy men andconcluded that higher blood levels of long-chain n-3 fattyacids were associated with a reduced risk of prostate cancer[34] Szymanski et al conducted ameta-analysis of fish intakeand prostate cancer by focusing on the incidence of prostatecancer and prostate cancer-specific mortality Their resultsdid not establish a protective association of fish consumptionwith prostate cancer incidence but showed a significant 63reduction in prostate cancer-specific mortality [35]

The results of correlational studies are mixed someof them failing to demonstrate a statistically significanteffect Several confounding factors could account for theinconsistent results on the association between n-3 PUFAand prostate cancer First population-based studies mainlyrely on data from self-reported dietary fatty acid intake orfrom estimates based on national consumption and theseassessments correlate poorly with direct measurements offatty acids in patient samples In addition the actual intakein n-3 PUFA may be too low for a protective effect in somecases Second the ratio of n-6 to n-3 fatty acids may bemore important than the absolute amount of n-3 PUFAas suggested by animal and human studies [16 36] Usinga prostate-specific Pten knockout mouse prostate cancermodel we showed that a ratio of n-6 to n-3 below 5 waseffective in slowing cancer progression [3] Brown et alreported that AA might potentiate the risk of metastaticprostate cancer cell migration and seeding at the secondarysite in vivo and lowering the n-6n-3 ratio in diet by uptakeof n-3 PUFA might reduce this risk [37]

4 Mechanisms of Action

41 Integration of PUFAs into PlasmaMembrane Glycerophos-pholipids Although fatty acids are consumed at high levelsin a typical Western diet tumor cells display a strong










2by PTEN



3AkT




























5 Conclusions



Abbreviations




References




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology










2by PTEN



3AkT




























5 Conclusions



Abbreviations




References




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















5 Conclusions



Abbreviations




References




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



References




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article mechanisms of omega-3 polyunsaturated fatty...

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