Autophagy or Apoptosis: Anticancer Molecular Mechanism of Epigallocatechin Gallate with Natural Polyphenol Effect on HepG2 Cells Viability
DOI:
https://doi.org/10.31351/vol32iss1pp167-176Keywords:
Epigallocatechin gallate; EGCG; apoptosis; autophagy; HepG2; cancer cell.Abstract
Background: The anticancer impact of Epigallocatechin gallate (EGCG) the highly active polyphenol of green tea was abundantly studied. Though, the exact mechanism of its cytotoxicity is still under investigation. Objectives: Hence, the current study designed to investigate the molecular target of EGCG in HepG2 cells on thirteen autophagy- and/or apoptosis- related genes. Methods: The apoptosis detection analyses such as flow cytometry and dual apoptosis assay were used. The genes expression profile was explored by the real-time quantitative-PCR. Results: EGCG increases G0/G1 cell cycle arrest and the real-time apoptosis markers proteins leading to stimulate apoptosis in 70% of the treated HepG2 cells. The up-regulation was recorded in two of autophagy inhibitory genes (FOS-1, FOS-2) and apoptosis inducer gene (DDIT3). While the other ten genes expressed down-regulation after treatment. The down regulation was manifested in the genes of mitochondrial autophagy marker proteins (BNIP3, BNIP3L, and NBR1), the autophagy regulator genes (BIRC5, MAPK9), and the gene that implicated in protein biosynthesis and protein modification (ITGB1). The genes that have pro-apoptotic function in cells (CAPNS1, CFLAR, EIF4G, and RB1) were also showed down-regulation after treatment. Conclusion: Thus, the results demonstrated a potential effect of EGCG to induce apoptosis rather than autophagy in the treated HepG2 cells that could play a good target for therapy.
How to Cite
Publication Dates
References
Siegelin MD, Habel A, Gaiser T. Epigalocatechin-3-gallate (EGCG) downregulates PEA15 and thereby augments TRAIL-mediated apoptosis in malignant glioma. Neurosci Lett. 2008;448(1):161-5.
Liu Q, Qian Y, Chen F, Chen X, Chen Z, Zheng M. EGCG attenuates pro-inflammatory cytokines and chemokines production in LPS-stimulated L02 hepatocyte. Acta Biochim Biophys Sin (Shanghai). 2014;46(1):31-9.
Modernelli A, Naponelli V, Giovanna Troglio M, Bonacini M, Ramazzina I, Bettuzzi S, et al. EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism. Sci Rep. 2015;5:15270.
Mi Y, Qi G, Fan R, Qiao Q, Sun Y, Gao Y, et al. EGCG ameliorates high-fat- and high-fructose-induced cognitive defects by regulating the IRS/AKT and ERK/CREB/BDNF signaling pathways in the CNS. FASEB J. 2017;31(11):4998-5011.
Dhatwalia SK, Kumar M, Dhawan DK. Role of EGCG in Containing the Progression of Lung Tumorigenesis - A Multistage Targeting Approach. Nutr Cancer. 2018;70(3):334-49.
Zhao L, Liu S, Xu J, Li W, Duan G, Wang H, et al. A new molecular mechanism underlying the EGCG-mediated autophagic modulation of AFP in HepG2 cells. Cell Death Dis. 2017;8(11):e3160.
Zhou DH, Wang X, Feng Q. EGCG enhances the efficacy of cisplatin by downregulating hsa-miR-98-5p in NSCLC A549 cells. Nutr Cancer. 2014;66(4):636-44.
Zhu J, Wang M, Hu D. Development of an autophagy-related gene prognostic signature in lung adenocarcinoma and lung squamous cell carcinoma. PeerJ. 2020;8:e8288.
Xu WS, Li T, Wu GS, Dang YY, Hao WH, Chen XP, et al. Effects of furanodiene on 95-D lung cancer cells: apoptosis, autophagy and G1 phase cell cycle arrest. Am J Chin Med. 2014;42(1):243-55.
Liao A, Hu R, Zhao Q, Li J, Li Y, Yao K, et al. Autophagy induced by FTY720 promotes apoptosis in U266 cells. Eur J Pharm Sci. 2012;45(5):600-5.
Wang N, Feng Y. Elaborating the role of natural products-induced autophagy in cancer treatment: achievements and artifacts in the state of the art. Biomed Res Int. 2015;2015:934207.
Cory AH, Owen TC, Barltrop JA, Cory JG. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun. 1991;3(7):207-12.
Siddik ZH. Checkpoint controls and targets in cancer therapy. Totowa, N.J.: Humana Press; 2010. xiv, 273 p. p.
Balijepalli MK, Tandra S, Pichika MR. Antiproliferative activity and induction of apoptosis in estrogen receptor-positive and negative human breast carcinoma cell lines by Gmelina asiatica roots. Pharmacognosy Res. 2010;2(2):113-9.
Desjardins LM, MacManus JP. An adherent cell model to study different stages of apoptosis. Exp Cell Res. 1995;216(2):380-7.
Ahn JI, Jeong KJ, Ko MJ, Shin HJ, Chung HJ, Jeong HS. High-concentration Epigallocatechin Gallate Treatment Causes Endoplasmic Reticulum Stress-mediated Cell Death in HepG2 Cells. Genomics Inform. 2009;7(2):97-106.
Guan G, Yang L, Huang W, Zhang J, Zhang P, Yu H, et al. Mechanism of interactions between endoplasmic reticulum stress and autophagy in hypoxia/reoxygenationinduced injury of H9c2 cardiomyocytes. Mol Med Rep. 2019;20(1):350-8.
Shlomovitz I, Speir M, Gerlic M. Flipping the dogma - phosphatidylserine in non-apoptotic cell death. Cell Commun Signal. 2019;17(1):139.
Mayr C, Wagner A, Neureiter D, Pichler M, Jakab M, Illig R, et al. The green tea catechin epigallocatechin gallate induces cell cycle arrest and shows potential synergism with cisplatin in biliary tract cancer cells. BMC Complement Altern Med. 2015;15:194.
Paglin S, Yahalom J. Pathways that regulate autophagy and their role in mediating tumor response to treatment. Autophagy. 2006;2(4):291-3.
Kocaturk NM, Akkoc Y, Kig C, Bayraktar O, Gozuacik D, Kutlu O. Autophagy as a molecular target for cancer treatment. Eur J Pharm Sci. 2019;134:116-37.
Wang JD, Cao YL, Li Q, Yang YP, Jin M, Chen D, et al. A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation. Autophagy. 2015;11(11):2057-73.
Yogev O, Goldberg R, Anzi S, Yogev O, Shaulian E. Jun proteins are starvation-regulated inhibitors of autophagy. Cancer Res. 2010;70(6):2318-27.
Wang Z, Zhang H, Liu Z, Ma Z, An D, Xu D. Apigenin attenuates myocardial infarction-induced cardiomyocyte injury by modulating Parkin-mediated mitochondrial autophagy. J Biosci. 2020;45.
Xu Y, Shen J, Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy. 2020;16(1):3-17.
Belousov DM, Mikhaylenko EV, Chubarev VN, Tarasov VV, Somasundaram SG, Kirkland CE, et al. The Dawn of Mitophagy: What Do We Know by Now? Curr Neuropharmacol. 2020.
Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009;33(4):505-16.
Deosaran E, Larsen KB, Hua R, Sargent G, Wang Y, Kim S, et al. NBR1 acts as an autophagy receptor for peroxisomes. J Cell Sci. 2013;126(Pt 4):939-52.
Lin TY, Chan HH, Chen SH, Sarvagalla S, Chen PS, Coumar MS, et al. BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy. 2019:1-18.
Wan B, Liu B, Yu G, Huang Y, Lv C. Differentially expressed autophagy-related genes are potential prognostic and diagnostic biomarkers in clear-cell renal cell carcinoma. Aging (Albany NY). 2019;11(20):9025-42.
Barutcu SA, Girnius N, Vernia S, Davis RJ. Role of the MAPK/cJun NH2-terminal kinase signaling pathway in starvation-induced autophagy. Autophagy. 2018;14(9):1586-95.
Ren L, Mo W, Wang L, Wang X. Matrine suppresses breast cancer metastasis by targeting ITGB1 and inhibiting epithelial-to-mesenchymal transition. Exp Ther Med. 2020;19(1):367-74.
Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ. eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol. 2008;181(2):293-307.
Fan S, Li Y, Yue P, Khuri FR, Sun SY. The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP Down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. Neoplasia. 2010;12(4):346-56.
Andrieu C, Taieb D, Baylot V, Ettinger S, Soubeyran P, De-Thonel A, et al. Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E. Oncogene. 2010;29(13):1883-96.
MacLeod JA, Gao Y, Hall C, Muller WJ, Gujral TS, Greer PA. Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib. Oncotarget. 2018;9(70):33382-95.
Demarchi F, Bertoli C, Copetti T, Eskelinen EL, Schneider C. Calpain as a novel regulator of autophagosome formation. Autophagy. 2007;3(3):235-7.
Humphreys L, Espona-Fiedler M, Longley DB. FLIP as a therapeutic target in cancer. FEBS J. 2018;285(22):4104-23.
He MX, He YW. A role for c-FLIP(L) in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes. Cell Death Differ. 2013;20(2):188-97.
Fan G, Steer CJ. The role of retinoblastoma protein in apoptosis. Apoptosis. 1999;4(1):21-9.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Iraqi Journal of Pharmaceutical Sciences ( P-ISSN 1683 - 3597 E-ISSN 2521 - 3512)
This work is licensed under a Creative Commons Attribution 4.0 International License.
