reactive oxygen species (ros) an activator of apoptosis and autophagy

Kashyap et al. 2016 Scienceindoors Publishers

Submit your Manuscript: www.scienceindoors.com J. Biol. Chem. Sci. 2016, 3(2), 256-264

Tapan K. Mukherjee3 1Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, India-160012. 2Department of Chemistry, Career Point University, Tikker-Kharwarian, Hamirpur, Himachal Pradesh 176041, India. 3Department of Biotechnology, M.M. University, Mulana, Ambala, Haryana, India. 4Department of Biochemistry, Delhi University, South-Campus, New Delhi, India. 5Department of Chemistry, MM University, Sadopur, India. *Corresponded author: Dr. Hardeep Singh Tuli, Assistant Professor, M.M. University, Mulana, Ambala, Haryana, India. Email: [email protected] Received: November 6, 2016 Accepted: December 2, 2016

Introduction

Reactive oxygen species (ROS) are the oxygen containing species like O2-, OH− with free unpaired electrons which make them highly energetic and reactive. Their formation and elimination in the healthy cells is constant, which is obligatory for the well-functioning of many biological processes [1]. These species are generated by the different modes such as by mitochondria-dependent manner, NADPH oxidase, cytokines, growth factors (HGF and TGF-β), and tumor promoters (12-O-tetradecanoylphorbol-13-acetate or TPA) [2]. The leaking of electrons from complex III of mitochondrial electron transport chain during the respiration, also increase the production of ROS. A particular concentration of generating ROS plays crucial role in different cancer process. At high concentration they activate oxidative stress, apoptosis which leads to cell death, on contrast their low concentration activate the angiogenesis and initiate invasion and metastasis of tumor cells [3, 4]. Generated ROS cause damage to the tissues in various forms, including induction of oxidative stress which causes cardiovascular disease, neuro-degeneration and leads to carcinogenesis by causing damage to DNA, lipids, and cellular proteins [5]. ROSs are important inhibitors of cancer cell proliferation via apoptosis inducer. Elevated production of ROS in cancer cells

induces apoptosis or autophagy [6]. Most of the treatment therapies for cancer include the elevation of ROS by antioxidant system suppression in the cancer cells to target the self-renewal of cancer stem cells (CSC), epithelial-mesenchymal transition (EMT), and angiogenesis [7-9]. Several studies support the phenomenon of NADPH blockage or inhibition in the tumor cell that help tumor cell to evade elevated ROS, which could be reverse as an anti-tumor approach [2]. The present review article is subjected to comprehensively describe associations of ROS with cancer processes like apoptosis, autophagy and their potential implication in the development of novel anti-cancer drugs. Role of reactive oxygen species in apoptosis Apoptosis, a programmed cell death having two well defined intrinsic and extrinsic pathways, is required for tissue morphogenesis during early embryonic development [10–12]. Intrinsic and extrinsic pathways of apoptosis involve the mitochondrial membrane disruption which releases Cyt-c in the cytoplasm, activates caspase-9, 3 and induce FAS receptor and caspase 8 respectively [13-19]. It has been demonstrated that ROS generation induces both the apoptotic pathways by regulation caspase cascade and activating Fas and ERK 1/2 and p38 MAPK signaling

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Review article

Reactive Oxygen Species (ROS): an Activator of Apoptosis and Autophagy in Cancer

Abstract Despite significant improvements in the technical aspects of cancer diagnosis and management, it is still a leading cause of mortality worldwide. Although, the development of a variety of therapeutic strategies with effective mechanisms of action is increasing, the advanced understanding of molecular mechanisms of cancer initiation and progression is still the important consequence. Reactive oxygen species (ROS) with great concern due to the ability to modulate cell survival and cell death signaling pathways are could be considered to design the effective anti-cancer strategies. Several anti-cancer agents used for the treatment of various cancers regulates ROSs generation which subsequently modulate the pro-apoptotic molecules, expression of various transcription factors including Sp1, AP1, NF-kβ, and other pro-oncogenic genes that are engaged in cancer cell proliferation, survival and metastasis. Concentration dependent ROS has distinct role in different cancer processes like in apoptosis, cancer survival, autophagy, angiogenesis, metastasis, and inflammation. Radiation and potent agents used in chemotherapy are working on the phenomenon of ROS generation that inhibit cancer process. With the intense understanding of ROS’s role in the particular cancer process which is inevitable in cancer, may be used in health care to improve patient’s survival rate. The current review presents all the proposed molecular interactions of ROS with their known cellular targets in cancer cell.

Dharambir Kashyap1, Ajay Sharma2, Vivek kumar Garg1, Hardeep Singh Tuli3*, Gaurav Kumar4, Manoj Kumar5



pathways [6, 20–25]. Several studies done so far demonstrated the ROS-mediated apoptosis activation as a consequence of loss of mitochondrial membrane potential, release of Cyt-c, activation of caspase 9, 3, cleavage of PARP and down-regulation of Bcl2 and up-regulation of pro-apoptotic protein Bax in LLC-PK1, A2058, A375, and A875 cells [26–28]. An in-vitro study with melanoma cells revealed the involvement of Akt and p38 MAPK pathway in ROS-mediated apoptosis [29-30]. Similarly, study using natural product as a potent anticancer molecule determined the ROS-mediated activation of ERK, JNK, and p38 MAPK leading to the activation of caspase-3 in Gastric cancer BGC-823 cells and multiple myeloma U266 cells [31-32]. Moreover, ROS-mediated apoptosis was also observed in CML-T1 leukemia cells and peripheral blood lymphocytes [33]. Additionally, Keswani et al., 2014 noticed ROS-dependent apoptosis in Palladium(II) complex-treated A-549 lung cancer cells [34]. Recently, Yao et al., 2015 reported 23-hydroxybetulinic acid derivative B4G2-induced depolarized mitochondrial membrane potential, released Cyt-c, activated caspase-9 and caspase-3 and cleaved poly ADP-ribose polymerase (PARP), and increased concentration of intracellular

Ca2+ and ROS which activated the apoptosis in the liver cancer cells [35]. In addition, Dixit et al., 2014 suggested ROS-mediated apoptosis in glioma cells as a consequence of Yes-associated protein 1 (YAP1), ATM and JNK activation [36]. Moreover, ROS-mediated endoplasmic reticulum (ER) stress was additionally found to be associated with apoptosis initiation in carnosic acid-treated human renal carcinoma Caki cells [37]. In another study using head and neck carcinoma, the anticancer agent dihydromyricetin (DHM) leads which increases p-STAT3-dependent apoptosis by ROS generating signaling pathways has noticed [38]. Tideglusib another anticancer molecule has been reported to be a dose dependent activator of pro-apoptotic proteins (PARP, Caspase-9, Caspase-7, Caspase-3) and tumor-related genes (FasL, TNF-α, Cox-2, IL-8, Caspase-3) in human neuroblastoma IMR32 cells through the generation of ROS [39]. In human epithelial ovarian cancer cell lines OAW42 and OVCAR3 apoptosis induction was correlated with increased ROS generation under the effect of cocoa procyanidin [40]. Su et al., 2016 also indicated the apoptotic effect of carnosoic acid in in-vitro as well as in-vivo cervical cancer model via promoting ROS and activating JNK

Figure 1: Endogenously, increased metabolic activity, peroxisome activity, increased cellular receptor signaling, oncogene activity, cyclooxygenases, lipoxygenases, thymidine phosphorylase, endoplasmic reticulum (ER) system, and NADPH oxidase (NOX) complex, and exogenously ultraviolet radiation (UVR), ionizing radiation (IR) and hypoxia are the prominent factors for ROS generation. To counter the production of these ROS inducers, cells possess their scavenger systems in the forms of SOD, catalase, and Gpx to maintain the homeostasis.



signaling pathways [41]. Thus, great evidence supporting and suggesting the phenomenon of ROS mediating apoptotic cell death which could be an effective treatment approach for cancer cure. Role of reactive oxygen species in autophagy Autophagy is an evolutionarily conserved catabolic process which involves degradation of cellular components such as proteins and organelles in lysosomes and serve as an alternative source of energy during metabolic stress to maintain cellular homoeostasis and survival [42]. Considering its crucial role in cell death, autophagy may be used as an alternative and promising therapeutic target for cancer in apoptosis-resistant malignancy [43-45]. Till date, more than 34 types of different proteins and many signaling pathways has identified and characterized which could induce autophagy process [46–48]. Growing evidence has suggested the involvement of ROSs in the modulation of various autophagy regulating proteins such as ATG4, AMPK and NF-kβ and in cancer inhibition [49, 50]. Various natural and synthetic molecules are associated with the inhibit of cancer proliferation through ROS-mediated autophagy induction [51, 52]. BNIP3 (Bcl2 nineteen-kilodalton

interacting protein), a stress-induced protein has been found to be up-regulated by ROS in a number of cancers [53–58]. Autophagy-cognate gene (Atg4) is another important autophagy triggering protein which is activated by ROS and consequently up-regulates the expression of LC3-II which required to initiat an autophagosome formation [59–61]. Zhang et al., 2008 investigated the role of hypoxia-induced mitochondrial ROS in in-vitro and in-vivo model and reported the activation of BNIP mediated Beclin-1 and Atg5 which subsequently induced cell death [62, 63]. Investigating MCF-7 cells, Angela Alexander et al., determined that elevated ROS could induce autophagy by activating ATM-mediated TSC2 tumor suppressor gene via LKB1-AMPK-mTORC1 signaling pathway [64]. In a study, using human osteosarcoma cell line (MG63), Guang-rong Ji et al., 2015 noted the involvement of PERK in stress-induced autophagy through inhibition of mTOR pathway [65]. In recent years, a number of chemotherapeutic and phytochemicals agents have developed that are potent modulators of ROS-mediated autophagy signaling pathways [43, 66–72] For example, oleanoic acid trigger the ROS generation in HepG2 and SMC7721 cells and activate the autophagy confirmed by

Figure 2: ROS generated by endogenously or exogenously means can activate both intrinsic and extrinsic apoptosis pathways. MAPK, Bax, and Bcl2 cell signaling molecules modulation in response to the ROS activate the downstream caspase cascades which further resulted in apoptotic cell death.



increased distribution of LC3 and an increased ratio of LC3-II to LC3-I in these cancer cell [73]. Similarly Macranthoside B, has been known to induced the autophagy mediated cancer cell death by modulating the ROS/AMPK/mTOR pathway in A2780 human ovarian carcinoma cell [74]. In addition, the studies also identified the ROS-dependent activation of autophagy in glioma cell and HepG2 cells by modulation of PI3K/Akt and MAPK signaling pathways [63, 75, 76]. Moreover, PLB a naturally occurring naphthoquinone process the anti-cancer by Sirt1 and PI3K/Akt/mTOR-mediated autophagy in PC-3, DU145, and SCC25 cells [77, 78]. Further, L Zhang et al. 2014 relevealed the autophagy induction depending on suppression of the PI3K/AKT/mTOR/p70S6K and activation of JNK signaling pathways via ROS arbitrated after the treatment of human glioblastoma cells by cathepsin-S [79]. In the similar way, nimbolide, an active molecule from Azadirachta indica, has been reported to exhibits anti-proliferative properties mediated by ROS generation that reduce PI3K/AKT/mTOR and ERK signaling in pancreatic cancer [80]. Conclusion and future perspectives ROS are considered to be essential cellular molecules in order to maintain physiological homeostasis. Evidence has suggested that low levels of ROS play a significant role in cellular signaling by acting as a secondary messenger, whereas at higher

concentrations ROS could act as potent anti-cancer agents. Numerous chemotherapeutic drugs have been found to induce cell death by activating ROS generation [81–83]. Furthermore, in comparison to non-transformed cells, cancer cells have been found to have moderately elevated levels of both ROS as well as antioxidant molecules [84, 85]. Therefore, conventional ROS-mediated anticancer therapies may fail in cancer cells due to abundant presence of antioxidant molecules. Using compounds with inhibitory effects on antioxidant enzymes could thus play an important role in the ROS-mediated fight against neoplasms opening new perspectives in cancer research [86,87]. Therefore, to develop an efficient anti-cancer treatment modality, the scientific community should completely understand the redox state of the tumor. This means that cellular mechanisms involved in the production of ROS and their downstream regulated molecular targets and signaling pathways urgently need to be unraveled. Acknowledgements The authors fully acknowledge Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh and Maharishi Markandeshwar University, Mullana-Ambala and for providing the requisite facility to carry out the study. Conflict of interest The authors have declared no conflicts of interest.

Figure-3: ROS-mediated activation of autophagy by autophagosome formation is controlled by various factors including mTOR/Akt, AMPK, VPS34, beclin 1, and PERK which has been known to be modulated by ROS generation.



Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. References

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reactive oxygen species (ros) an activator of apoptosis and autophagy

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