Animal Lectins: Potential Antitumor Therapeutic Targetsin Apoptosis

Zhe Liu & Qian Zhang & Hao Peng & Wen-zhi Zhang

Received: 11 December 2011 /Accepted: 10 July 2012# Springer Science+Business Media, LLC 2012

Abstract Lectins, a group of carbohydrate-binding proteins ubiquitously distributed intoplants and animals, are well-known to have astonishing numerous links to human cancers. Inthis review, we present a brief outline of the representative animal lectins such as galectins, C-type lectins, and annexins by targeting programmed cell death (or apoptosis) pathways, and alsosummarize these representative lectins as possible anti-cancer drug targets. Taken together,these inspiring findings would provide a comprehensive perspective for further elucidating themultifaceted roles of animal lectins in apoptosis pathways of cancer, which, in turn, mayultimately help us to exploit lectins for their therapeutic purposes in future drug discovery.

Keywords Lectin . Cancer . Apoptosis . Galectin . C-type lectin . Annexin

Introduction

Lectins, a group of highly diverse non-immune origin proteins ubiquitously distributed inplants, animals, and fungi, contain at least one non-catalytic domain which enables them toselectively recognize and reversibly bind to specific free sugars or glycans present onglycoproteins and glycolipids without altering the structure of carbohydrate [1]. Animallectins (endogenous) have been drawing a rising attention for their multifaceted rolesimplicated in the extrinsic and intrinsic apoptotic pathways in cancer; therefore, they wouldbe further used not only as biomarkers but as potential targets for cancer therapeutics [2].Among these, galectin-1 (Fig. 1a), P-selectin (Fig. 1b), and annexin-1 (Fig. 1c) are most

Appl Biochem BiotechnolDOI 10.1007/s12010-012-9805-6

Z. Liu :W.-z. Zhang (*)Department of Hepatobiliary Surgery, General Hospital of PLA, Beijing 100853, Chinae-mail: sn3064@163.com

Q. ZhangSchool of Life Sciences, Sichuan University, Chengdu 610064, China

H. Peng (*)BeiGene (Beijing) Co., Ltd, Beijing 102206, Chinae-mail: zhaoxu1986sc@163.com

closely associated with some core apoptosis-related pathways as potential anti-cancer drugtargets [3].

In this review, we present a brief outline of the representative animal lectins (e.g.,galectins, C-type lectins, and annexins) as potential targets implicated in the apoptoticpathways in cancer. To sum up, these findings may provide a better understanding ofthe roles of animal lectins in apoptosis of human cancers, thus, helping us exploitdiverse origin lectins as potential targets for future preclinical and clinical therapies ofcancer (Table 1).

Galectins

Galectins, a family of galactose-binding lectins known as Ca2+-independent S-type animallectins, are widely distributed in many types of mammalian cells [4]. To date, there havebeen 15 kinds of galectins identified to possess a carbohydrate recognition domain (CRD)and bind to N-acetyllactos probably via recognizing the β-gal unit. According to the numberand arrangement of the CRDs, galectins are classified into three main types. First is theproto-type galectins that contain two non-covalent homodimers of CRDs which can cross-link ligands on cell surfaces and extracellular matrix [5], including galectins-1, -2,-5, -7, -10,-11, -13, and -14 [6]. Another is the chimera-type galectin that possesses a combinedstructure including a C-terminal CRD and tyrosine-rich N-terminal domain which help toconstruct higher order oligomers [7]. As far as we know, only galectins-3 has been classifiedinto this group [8]. The tandem repeat galectins have two distinct CRDs and galectins-4, -6, -8, -9, and -12 [9] are in this group. Galectins bind β-galactosides through evolutionarilyconserved sequence elements of the carbohydrate recognition domain (CRD). Eachgalectin has an individual carbohydrate-binding preference in cytoplasm and nucleus,respectively. In the recent years, several reports have indicated that the correlationsbetween galectins and tumor progression are remarkable, indicating that galectins canbe used as potential biomarkers and even potential targets for cancer diagnosis andtherapy [10]. Of note, galectins, located in the cytoplasm and nucleus, can secreteoutside the cells and function extracellularly. Some galectins have been reported tobind to several cell surface antigens and receptors in a carbohydrate-dependent style.Moreover, galectins have been demonstrated to function inside cells in response to itscarbohydrate-binding activities. As mentioned above, galectins may regulate cellsignal transduction by binding intracellular ligands and participating in several apo-ptotic pathways in cancer.

Fig. 1 The structures of three representative animal lectins. a Molecular structure of galectin-1; b molecularstructure of P-selectin; c molecular structure of annexin-1

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Galectin-1 and galectin-3

Galectin-1 contains two non-covalent homodimers of CRDs cross-linking ligands on cellsurfaces and extracellular matrix, and its crystal structure of human galectin-1 consists of asix-stranded and a five-stranded β-sheet in an antiparallel arrangement [11]. Galectin-1 mayfavor tumor growth and lead to tumor progression and metastasis by influencing variousbiological processes such as cell migration, adhesion, angiogenesis, and apoptosis [12] sinceit can conjugate to H-Ras and promote its location to the plasma membrane which is a keyprocedure of tumor transformation [13], and thus resulting in sustained activation of Raf-1and MAPK-1 that play the key promoters in apoptosis [14]. Moreover, galectin-1 expressionhas been examined in several malignant tumors including breast cancer, neuroblastoma, oral

Table 1 Animal lectins as possible therapeutic antitumor targets

Animal lectin Cancer type Mechanism Reference

Galectin-1 Breast carcinoma,colon carcinoma,ovary cancer,bladder carcinomas,gliomas, endometrialadenocarcinoma, head,and neck cancers,prostate carcinoma

Contribute to cell migration,adhesion, angiogenesis,tumor immune escape,induce apoptosis

[18, 19]

Galectin-3 Thyroid, central nervoussystem, head and necksquamous cell carcinoma,pancreas, bladder, stomach,and renal carcinoma,hepatocellular, ovary, breast,endometrium, skin, colon,prostate, salivary glands cancer

Involve in cell transformationand growth, inhibition ofapoptosis, affect tumorinvasion and metastasis

[20, 21]

Galectin-7 Thyroid tumors, colon carcinoma Correlate with keratinocytedifferentiation, p53 stabilization,and apoptosis induction. increaseslymphoma metastasis

[22]

Galectin-8 Colon cancer Inhibit cell adhesion, suppressesmigration, modulate cell surfacereceptors, induce apoptosis

[23]

P-seletion Colon carcinoma, breast cancerPromote the proliferation,induce apoptosis

[24]

NK-receptor Renal cell carcinoma Induce tumor apoptosis throughTRAIL and Fas ligands(pre-clinical)

[25]

Annexin A3 Colorectal, prostate cancer An angiogenic factor thatinduces vascular endothelialgrowth factor productionthrough the HIF-1 pathway

[26]

Annexin A6 Squamous epithelial carcinoma,malignant melanomas

Acts as tumor suppressorby negative regulatingthe Ras–Raf–MAPKsignaling pathway

[27]

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squamous cell carcinoma, and lung adenocarcinoma [15–17]. Other examples of the roles ofgalectin-1 in tumor biology include modulation of tumor invasion in hepatocellular carci-noma cell lines [18]. Some reports have also shown that galectin-1 can promote proliferationand invasion of pancreatic cancer cells [19].

Galectin-3, the sole member of the chimera-type galectin which contains an N-terminalregion composed of short amine acid segments and a C-terminal CRD, lacks a signalsequence required for secretion through some classical secretary pathways. Recent reportshave shown that its translocation to the cytosolic side of the plasma membrane plays a keyrole in galectin-3 translocation [20], and galectin-3 binds to multivalent carbohybrate ligandson the cell surface, thus initiating various cellular signaling events and affecting variouscellular functions [21]. In contrast to the extracellular cell death signal triggered by galectin-1, the anti-apoptotic activity of galectin-3 might result from an intracellular function of thischimeric protein [22]. Moreover, numerous cytosolic molecules have been identified asgalectin-3 ligands. The first molecular detected as a galectin-3 ligand was Bcl-2, a moleculeinvolved in apoptosis [23], suggesting that Bcl-2 binds to galectin-3 through its CRD. Also,other apoptosis-related molecules have been reported to be novel galectin-3 binding ligands.In addition, CD95 (APO-1/Fas), a member of the death receptor family, was reported tointeract with galectin-3 by co-immunoprecipitation and confocal microscopic analysis [24].Nucling, a protein involved in apoptosis regulation, was identified as a novel galectin-3binding molecule, and Alix/Aip1 was identified as a galectin-3-binding partner in jurkatcells [25]. Galectin-3 can affect K-Ras protein and Akt protein, suggesting that cytosolicgalectin-3 is involved in regulation of cell proliferation, differentiation, survival, andapoptosis [26], while synexin was detected to interact with galectin-3 in human epithelialcells [27]. These findings reveal that mitochondria are new localization sites of galectin-3,indicating the intracellular function of galectin-3 in apoptosis. Moreover, galectin-3 canmediate endocytosis of β1 integrin (CD29) via a caveolae-like signaling pathway as well asendocytosis of AGE products. Galectin-3 can also bind to CD98 on the membrane andsubsequently induce cell apoptosis through Ca2+ influx pathway [28] (Fig. 2). Additionally,a recent report has shown that Gal-3 is consistently overexpressed in pancreatic cancer ascompared to both chronic pancreatitis and normal pancreas, and the overexpression ofgalectin-3 enhanced the resistance to apoptosis [29].

Other Galectins

Galectin-7, a one-CRD galectin mainly found in stratified squamous epithelium, is an earlytranscriptional target of the tumor-suppressor protein p53 [30]. A recent report has shownthat galectin-7 expression is upregulated after ultraviolet B irradiation of epidermal [31],resulting in p53 stabilization and apoptosis induction, which indicates that galectin-7 mayparticipate in the pro-apoptotic effects of p53 on keratinocytes. Moreover, galectin-7 canpromote JNK activation and mitochondrial cytochrome c release, a mitochondrial PCDpathway [32]. Moreover, recombinant galectin-8 can inhibit adhesion of human carcinoma1,299 cells to plates coated with integrin ligands and thus inducing cancer cell apoptosis [33](Fig. 2). Furthermore, by a cellular model of rheumatoid arthritis, some studies have shownthat galectin-8 can induce apoptosis in synovial fluid cells, possibly by interacting specif-ically with the CD44vRA isoform of CD44 [34]. Galectin-9 is a two-CRD galectin with itsthree isoforms differing in the lengths having been identified. Recombinant galectin-9induces apoptosis in thymocytes, in a dose-dependent and lactose-inhibitable manner [35].The apoptosis component p38 is also an important mediator of galectin-9-induced dendriticcell maturation [36].

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C-Type Lectins

C-type lectin s, a superfamily of mammalian lectins mainly including selectin, DC-SIGN,and NK-receptors have been linked to various biological processes such as immuneresponses modulation, adhesion, proliferation, and apoptosis [37]. Selectin is the mostimportant member of C-type lectin, including P-selectin, L-selectin, and E-selectin. Amongthem, P-selectin was reported to promote the proliferation of colon carcinoma through p38and PI3K signaling pathways, suggesting that a complex made up of activated PI3K and p38can result in activation of integrin dependent on P-selectin and then happen with P-selectin-mediated cell spreading. Integrins have been shown to have a close relationship withcytoskeleton, which might play important roles as signal-transducting receptors, acti-vating different biochemical pathways such as MAPK cascade, and thus regulatingcell activation, proliferation, and apoptosis [38]. Additionally, other studies alsorevealed that PI3K and p38 signaling pathways activated by various stimuli playedeither a direct or an indirect role in tumor evolution. For instance, insulin-like growthfactor could activate PI3K and p38 pathways in breast cancer migration [39]. Withinthis context, heregulin-mediated-PI3K and -p38 activation could facilitate the activa-tion of the matrix metalloproteinase (MMP)-2 [33] and MMP-9 [37], as significantproteins in tumor invasion [38]. After its adhesion to colon carcinoma cells, E-selectincould promote tyrosine phosphorylation of various proteins including c-Src and p38MAPK [39, 40].

Fig. 2 Animal lectins are involved in the apoptotic pathways. In this context of cancer, to inhibit apoptosis,galectin-1 can combine with H-Ras to activate Raf-1/MEK-1/ERK signaling pathway. Galectin-3 have threeways to activate caspase-3 to induce apoptosis including binding to Bcl-1 to activate caspase-9, binding toCD95/Fas to enhance caspase-8 and combining with CD98 under Ca2+ influx. Galectin-3 can also bind to K-Ras to enhance PI3K/Akt pathway to inhibit apoptosis. Moreover, galectin-7 as well as Alix/AIP1 cancombine with JNK to promote caspase-9 and then caspase-3 to activate apoptosis. P-selectin either workson K-Ras or PI3K to inhibit apoptosis. In addition, Annexin can regulate several signaling pathways to inhibitapoptosis. Annexin A1 can activate IKK and then NF-κB. Annexin A3 can promote HIF-1αand Annexin A6can activate Raf-1/MEK-1/ERK pathway

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It is well-known that special location dooms DC-SIGN to involve in immune responsesand modulate signaling pathways with counter-ligand. Recent studies have revealed thatrestraint of DC-SIGN by specific antibodies can contribute to ERK1/2 and Akt phosphor-ylation without concomitant p38 activation [41]. Furthermore, DC-SIGN co-precipitateswith the tyrosine kinases Lyn and Syk, indicating that DC-SIGN acts as intracellularsignaling molecules triggering activation of ERK1/2, Lyn, Syk, etc. [42]. GlycosylatedICAM-2 can recognize and bind to DC-SIGN, forming a DC-SIGN-ICAM-2 complex toinitiate the maturation of DCs which can induce specific cytotoxic T lymphocyte-modulatedantitumor immune response. Besides, PI3K activation mediates NF-κB-induced dendriticcell maturation [43]. Of note, NK cells can directly induce tumor apoptosis via perforingranzyme pathway or death receptors such as TRAIL and Fas ligands which are produced ontumor cell surfaces [44]. Therefore, the sensitization of tumor target cells to NK cell-mediated apoptosis can present a novel drug target for cancer therapy (Fig. 2).

Annexins

The annexins are a superfamily of Ca2+-regulated phospholipid-binding proteins of 70amino acid residues [45]. The annexins are composed of two main structural domains: thevariable amino-terminus mediating interactions with protein ligands, as well as the con-served carboxyl terminus containing the calcium-binding and membrane-binding sites [46].They have a diverse range of cellular functions including apoptosis, inflammation, andgrowth regulation [47]. Current changes in the expression of individual annexins, except forannexin A9 and annexin A13, have been observed in different types of cancer, implicatingthe changes in annexin expression and/or their subcellular localizations in tumor develop-ment and progression, especially tumor invasion and metastasis, as well as angiogenesis anddrug resistance.

Annexin A1 is a major substrate for epidermal growth factor receptor kinases and serine/threonine kinases, and it is involved in a range of cellular signal transduction pathways, suchas inflammation, cell differentiation, cell proliferation, and tumor invasion [48]. The in-creased expression of annexin A1 can correlate with the increasing tumor stage as well as thepresence of metastases and poor survival [49], indicating its diagnostic value in certain typesof cancer, such as hairy cell leukemia [50]. Moreover, annexin A1 has also been used as apotential antitumor drug by inhibiting the NF-κB signal transduction pathway [51]. Cellsurface annexin A2, a receptor for both proteases and extracellular matrix proteins, couldoverexpress in several types of cancer, indicating a role in suppressing tumor invasion andmetastasis [52]. Paradoxically, it is also a receptor for angiostatin by blocking annexin A2-dependent plasmin production, suggesting a possible way to develop new anti-angiogenictherapies [53, 54]. Accordingly, annexins can play multiple roles in tumor development andprogression, which are relevant to tumor invasion and metastasis, as well as angiogenesisand apoptosis (Fig. 2).

Conclusions

Hitherto, a bulk of updated data demonstrates that lectins from animals have been widelyused as remarkable biomarkers and potential novel drug targets, respectively, in diagnosis,prognosis, and especially cancer therapy. Galectins, the most well-known animal lectins,have been gradually utilized not only as the key biomarkers for recognition of tumor

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initiation and progression from different stages, but as potential new targets that may playthe pivotal roles for regulation of cancer-related signaling pathways for anti-neoplastic drugdiscovery. In addition, C-type lectin receptors (CLRs), known as pattern recognition recep-tors implicated in cancer, have been found that their complex mechanisms which glycosyl-ation can be changed during inflammation, cancer progression, or apoptosis thus creatingnew opportunities of therapeutic intervention in the immune system. Thus, researching ingalectins and C-type lectins might contribute significantly to the understanding of the causesand mechanisms of carcinogenesis; hence, the thrust in research ought to be focused onelucidating molecular mechanisms of actions of galectins and C-type lectins implicated intheir interactions with other genes or proteins, focusing on the aim of providing leads todevelop more new sophisticated tools, as well as to improve the currently available means ofcancer detection and treatment.

Our understanding of the multifaceted roles of lectins in cancer has benefited from theavailability of all the above-mentioned data; however, there are significant disadvantagesinherent in the complex molecular mechanisms of lectins, as well as a pressing need formore additional key information. Thus, further discoveries are being driven by an abundanceof structural information on the potential drug targets; thereby, X-ray crystallography andnuclear magnetic resonance would be invaluable in the efforts to harness these lectins forcancer drug discovery. Therefore, the novel methods would help provide more novel insightsinto how these animal lectins could play the key roles as potential antitumor drugs or targetsin cancer treatment.

In summary, we have demonstrated a brief outline of representative animal lectins aspotential targets in cancer therapy. Therefore, these inspiring findings would provide acomprehensive perspective for the key roles of lectins from animals in cancer, which inturn may ultimately help cancer biologists and clinicians to exploit them for their therapeuticpurposes in future drug discovery.

Acknowledgments We are grateful to Miss Qian Liu (National University of Singapore) for her criticalreview on this manuscript. We also thank Miss Xin Wen (Sichuan University) for her good suggestion on thiswork. Additionally, this work was supported by the grants from the “Eleventh Five-year Plan” military specialfund (no. 08BJ01), the Young teacher's fund of Sichuan University (no. 2010SCU11066) and the ScienceFoundation for Post Doctorate Research of China (no. 20110491725).

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