[en] Tumor hypoxia is one of the features of tumor microenvironment that contributes to chemoresistance in particular
by cellular adaptations that modulate the apoptotic process. However, the mechanisms involved in this resistance
still need deeper understanding. In this study, we investigated the involvement of four transcription factors, c-Myc,
nuclear factor κB (NF-κB), p53, and c-jun/activator protein 1 (AP-1) in the hypoxia-induced resistance to etoposide in
HepG2 cells. Whereas the profile of c-Myc and NF-κB activity did not fit the effect of hypoxia on caspase 3 activity,
hypoxia decreased basal p53 abundance and DNA binding activity as well as p53 etoposide-induced activation.
Short interfering RNA (siRNA) silencing evidenced that p53 was required for etoposide-induced apoptosis under
normoxia. An inhibition of its activity under hypoxia could thus be responsible at least in part for the protection
observed under hypoxic conditions. Moreover, p53 was found to induce the expression of Bak1. We showed that
Bak1 was involved in the etoposide-induced apoptosis because Bak1 siRNA decreased it. Conversely, hypoxia
increased c-jun DNA binding activity in the presence of etoposide. siRNA-mediated silencing of c-jun increased the
responsiveness of cells to etoposide under hypoxia, as shown by an increase in caspase 3 activity and lactate
dehydrogenase release. These effects occurred in a p53-independent manner. These data evidenced that hypoxia
decreased the responsiveness of HepG2 cells to etoposide at least by two independent pathways involving p53
inhibition and c-jun activation.
Research center :
Unité de Recherche en Biologie Cellulaire
Disciplines :
Oncology
Author, co-author :
Cosse, Jean-Philippe ; Université de Liège - ULiège > GIGA-R : Epigénétique Cellulaire et Moléculaire
Ronvaux, Marie
Ninane, Noelle
Raes, Martine
Michiels, Carine
Language :
English
Title :
Hypoxia-Induced Decrease in p53 Protein Level and Increase in c-jun DNA Binding Activity Results in Cancer Cell Resistance to Etoposide
Publication date :
October 2009
Journal title :
Neoplasia
ISSN :
1522-8002
eISSN :
1476-5586
Publisher :
BC Decker, Hamilton Ont, Canada
Volume :
11
Pages :
976-986
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
FUNDP - Facultés Universitaires Notre-Dame de la Paix [BE]
Tredan O, Galmarini CM, Patel K, and Tannock IF (2007). Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99, 1441-1454.
Cosse JP and Michiels C (2008). Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem 8, 790-797.
Cummins EP and Taylor CT (2005). Hypoxia-responsive transcription factors. Pflugers Arch 450, 363-371.
Huang LE (2008). Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation. Cell Death Differ 15, 672-677.
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, and Moll UM (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11, 577-590. (Pubitemid 36385115)
Behrens A, Sibilia M, and Wagner EF (1999). Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21, 326-329. (Pubitemid 29124945)
Potapova O, Basu S, Mercola D, and Holbrook NJ (2001). Protective role for c-Jun in the cellular response to DNA damage. J Biol Chem 276, 28546-28553. (Pubitemid 37391569)
Cosse JP, Sermeus A, Vannuvel K, Ninane N, Raes M, and Michiels C (2007). Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines. Mol Cancer 6, 61. (Pubitemid 350226877)
Piret JP, Cosse JP, Ninane N, Raes M, and Michiels C (2006). Hypoxia protects HepG2 cells against etoposide-induced apoptosis via a HIF-1-independent pathway. Exp Cell Res 312, 2908-2920. (Pubitemid 44246949)
Sermeus A, Cosse JP, Crespin M, Mainfroid V, de Longueville F, Ninane N, Raes M, Remacle J, and Michiels C (2008). Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity. Mol Cancer 7, 27. (Pubitemid 351594154)
Lozano J, Menendez S, Morales A, Ehleiter D, LiaoWC,Wagman R, Haimovitz- Friedman A, Fuks Z, and Kolesnick R (2001). Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts. J Biol Chem 276, 442-448. (Pubitemid 32050337)
Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, et al. (1998). Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273, 9158-9167. (Pubitemid 28176206)
de Longueville F, Surry D, Meneses-Lorente G, Bertholet V, Talbot V, Evrard S, Chandelier N, Pike A, Worboys P, Rasson JP, et al. (2002). Gene expression profiling of drug metabolism and toxicology markers using a low-density DNA microarray. Biochem Pharmacol 64, 137-149. (Pubitemid 34775184)
Bode AM and Dong Z (2004). Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4, 793-805.
Kim JY, Ahn HJ, Ryu JH, Suk K, and Park JH (2004). BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1α. J Exp Med 199, 113-124. (Pubitemid 38076483)
Wu X, Bayle JH, Olson D, and Levine AJ (1993). The p53-mdm-2 autoregulatory feedback loop. Genes Dev 7, 1126-1132.
Thornborrow EC and Manfredi JJ (1999). One mechanism for cell type-specific regulation of the bax promoter by the tumor suppressor p53 is dictated by the p53 response element. J Biol Chem 274, 33747-33756.
Jackson P, Ridgway P, Rayner J, Noble J, and Braithwaite A (1994). Transcriptional regulation of the PCNA promoter by p53. Biochem Biophys Res Commun 203, 133-140. (Pubitemid 24281071)
Grimberg A,ColemanCM, ShiZ, BurnsTF,MacLachlanTK,WangW, and El-Deiry WS (2006). Insulin-like growth factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling. Cancer Biol Ther 5, 1408-1414.
Tan M, Li S, SwaroopM, Guan K, Oberley LW, and Sun Y (1999). Transcriptional activation of the human glutathione peroxidase promoter by p53. J BiolChem274, 12061-12066. (Pubitemid 129518469)
Tomasetti M, Andera L, Alleva R, Borghi B, Neuzil J, and Procopio A (2006). α-Tocopheryl succinate induces DR4 and DR5 expression by a p53-dependent route: implication for sensitisation of resistant cancer cells to TRAIL apoptosis. FEBS Lett 580, 1925-1931.
Zhan Q, Chen IT, Antinore MJ, and Fornace AJ Jr (1998). Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. Mol Cell Biol 18, 2768-2778. (Pubitemid 28183446)
Webster KA, Discher DJ, and Bishopric NH (1993). Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. J Biol Chem 268, 16852-16858. (Pubitemid 23230004)
Hettinger K, Vikhanskaya F, Poh MK, Lee MK, de Belle I, Zhang JT, Reddy SA, and Sabapathy K (2007). c-Jun promotes cellular survival by suppression of PTEN. Cell Death Differ 14, 218-229. (Pubitemid 46092225)
Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, and Wagner EF (2003). Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112, 181-192. (Pubitemid 36144108)
Bruick RK (2000). Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97, 9082-9087. (Pubitemid 30626677)
Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, Miller C, Demonacos C, Stratford IJ, and Dive C (2004). Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol 24, 2875-2889. (Pubitemid 38381277)
Fels DR and Koumenis C (2005). HIF-1α and p53: the ODD couple? Trends Biochem Sci 30, 426-429.
Piret JP, Minet E, Cosse JP, Ninane N, Debacq C, Raes M, and Michiels C (2005). Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis. J Biol Chem 280, 9336-9344. (Pubitemid 40409627)
Dong Z, Wang JZ, Yu F, and Venkatachalam MA (2003). Apoptosis-resistance of hypoxic cells: multiple factors involved and a role for IAP-2. Am J Pathol 163, 663-671. (Pubitemid 36909427)
Kilic M, Kasperczyk H, Fulda S, and Debatin KM (2007). Role of hypoxia inducible factor-1 α in modulation of apoptosis resistance. Oncogene 26, 2027-2038. (Pubitemid 46514744)
Eischen CM,Weber JD, Roussel MF, Sherr CJ, and Cleveland JL (1999). Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13, 2658-2669.
Eischen CM, Packham G, Nip J, Fee BE, Hiebert SW, Zambetti GP, and Cleveland JL (2001). Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene 20, 6983-6993. (Pubitemid 33052191)
Mitchell KO, Ricci MS, Miyashita T, Dicker DT, Jin Z, Reed JC, and El-Deiry WS (2000). Bax is a transcriptional target and mediator of c-myc-induced apoptosis. Cancer Res 60, 6318-6325. (Pubitemid 30952131)
Shiloh Y (2003). ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3, 155-168.
Hubert A, Paris S, Piret JP, Ninane N, Raes M, and Michiels C (2006). Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level. J Cell Sci 119, 3351-3362. (Pubitemid 44405220)
Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J, Karin M, Angel P, and Wagner EF (1999). Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev 13, 607-619. (Pubitemid 29131884)