Abstract
Cervical cancer is the second most common malignant neoplasm in women, in terms of incidence and mortality rates worldwide, and is associated with excessive inflammation. This involves the expression of both pro- and anti-apoptotic proteins that have varied effect on tumor growth and metastasis. The objective of the present study was to elucidate the effect of hydrogen peroxide (H2O2) on apoptotic signal molecules in vitro in SiHa and CaSki cell lines expressing the human papilloma virus 16 E6 protein, which causes the ubiquitin-mediated degradation of p53 protein and is thus p53 deficient. The p53 is known to act as a cellular stress sensor and triggers apoptosis. We demonstrate, here, that in HPV 16 positive cell lines apoptosis is triggered by upregulation of p73, which causes activation of pro-apoptotic Bax accompanied by down regulation of anti-apoptotic Bcl xl, release of cytochrome c from mitochondria and activation of caspases-9 and -3.
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Rosty C, Michal Sheffer M, Tsafrir D, Stransky N, Tsafrir I, Peter M, Crémoux P, Rochefordière A, Salmon R, Dorval D, Thiery J, Couturier J, Radvanyi F, Domany E, Sastre-Garau X (2005) Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma. Oncogene 24:7094–7104
Sigal A, Matas D, Almog N, Goldfinger N, Rotter V (2001) The C-terminus of mutant p53 is necessary for its ability to interfere with growth arrest or apoptosis. Oncogene 20(35):4891–4898
Irwin MS, Kaelin WG Jr (2001) p53 family update: p73 and p63 develop their own identities. Cell Growth Differ 12:337–349
Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Rad Biol Med 29(3–4):222–230
Troyano A, Sancho P, Ferna´ndez C, de Blas E, Bernardiand P, Aller P (2003) The selection between apoptosis and necrosis is differentially regulated in hydrogen peroxide-treated and glutathione-depleted human promonocytic cells. Cell Death Differ 10:889–898
Nagata S (2000) Apoptotic DNA fragmentation. Exp Cell Res 256:12–18
Finkel T, Holbrook N (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247
Sharma H, Sen S, Singh N (2005) Molecular pathways in the chemosensitization of Cisplatin by quercetin in human head and neck cancer. Cancer Biol Ther 4:949–945
Sen S, Sharma H, Singh N (2005) Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by mitochondrial pathway. Biochem Biophys Res Commun 295:24–30
Kuhar M, Sen S, Singh N (2006) Role of mitochondria in quercitin enhanced chemotherapeutic response in human NSCLC H520 cells. Anticancer Res 26(2A):1297–303
Matés JM, Sánchez-Jiménez FM (2000) Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Biol 32(2):157–170
Ishikawa Y, Kitamura M (2000) Antiapoptotic effect of Quercetin; intervention in the JNK and ERK mediated apoptotic pathway. Kidney Int 58:1078–1087
Lin A (2000) Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays 25(1):17–24
Raffeles J, Griffin M, Dickinson JM (2004) Activation of ERK1/2, JNK and PKB by Hydrogen peroxide in human SH-SY5Y neuroblast cells, role of ERK 1/2 IN Hydrogen peroxide induced cell death. Eur J Pharmacol 483:163–173
Davison K, Mann KK, Waxman S, Miller WH (2004) JNK activation is a mediator of arsenic trioxide induced apoptosis in acute promyelocytic leukemia cells. Blood 103:3496–3502
Hengstermann A, Linares LK, Ciechanover A, Whitaker NJ, Scheffner M (2001) Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. PNAS 98(3):1218–1223
Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promote cytochrome c dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42
Bergamaschi D (2003) p53 polymorphism influences response in cancer chemotherapy via modulation of p73 dependent apoptosis. Cancer Cell 3:387–342
Toshinori O, Akira N (2005) p73, a sophisticated p53 family member in cancer world. Cancer Sci 79:729–737
Gerry M, Xin l, Melina G (2003) Functional regulation of p73 and p63: development and cancer. Trends in Biochem Sci 64:663–670
Melino G, Bernassola F, Ronalli M, Yee K, Zong, WX, Corazzari M, Knight RA, Green DR, Thompson C, Hvousden K (2004) P73 induces apoptosis via PUMA trans activation and Bax mitochondrial translocation. J Biol Chem (279) 8076–8083
Cory S, Adams J M (2002) The BCL 2 family: regulators of cellular life or death switch. Nat Rev Cancer 2:647
Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB (2000) Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug induced apoptosis of human tumor cells. Cell Death Differ 7:102–111
Launay S, Hermine O, Fontenay M, Kroemer G, Solary E, Garrido C (2005) Vital function for lethal caspases. Oncogene 24:5137–5148
Fernandez C, Frank S, Wang L, Schroeder M, Liu S, Greene J, Cocito A, Amati B (2003) Genomic targets of the human c-Myc protein. Genes Dev 17:1115–1129
Mitchell KO, Ricci MS, Miyashita T, Dicker DT, Jin Z, Reed JC, El-Deiry WS (2000) Bax is a transcriptional target and mediator of c-Myc-induced apoptosis. Cancer Res 60:6318–6325
Jolly C, Morimot RI (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 92:1564–1572
Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684
Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15(22):2922–2933
Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promote cytochrome c dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42
Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012
Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Saski T, Elia AJ, Cheng, HY, Ravagnan L (2001) Essential role of the mitochondrial apoptosis induced factor in programmed cell death. Nature 410:549–555
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This work was supported by a senior research fellowship from CSIR to Mayank Singh and partially by grant from DBT.
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Singh, M., Singh, N. Induction of apoptosis by hydrogen peroxide in HPV 16 positive human cervical cancer cells: involvement of mitochondrial pathway. Mol Cell Biochem 310, 57–65 (2008). https://doi.org/10.1007/s11010-007-9665-5
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DOI: https://doi.org/10.1007/s11010-007-9665-5