Abnormal rates of growth together with metastatic potential and lack of susceptibility to cellular signals leading to apoptosis are widely investigated characteristics of tumors that develop via genetic or epigenetic mechanisms. Moreover, in the growing tumor, cells are exposed to insufficient nutrient supply, low oxygen availability (hypoxia) and/or reactive oxygen species. These physiological stresses force them to switch into more adaptable and aggressive phenotypes. This paper summarizes the role of two key mediators of cellular stress responses, namely p53 and HIF, which significantly affect cancer progression and compromise treatment outcomes. Furthermore, it describes cross-talk between these factors.

Masaryk Memorial Cancer Institute Regional Centre for Applied Molecular Oncology Zluty kopec 7 65653 Brno Czech Republic

Zobrazit více v PubMed

Liao D, Johnson RS. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 2007;26(2):281–290. doi: 10.1007/s10555-007-9066-y. PubMed DOI

Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–468. doi: 10.1126/science.1059817. PubMed DOI

Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16(12):1466–1471. doi: 10.1101/gad.991402. PubMed DOI PMC

Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012;12(1):9–22. PubMed PMC

Uchida T, Rossignol F, Matthay MA, Mounier R, Couette S, Clottes E, Clerici C. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem. 2004;279(15):14871–14878. doi: 10.1074/jbc.M400461200. PubMed DOI

Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J Exp Biol. 1998;201(Pt 8):1153–1162. PubMed

Fernandez-Sanchez R, Berzal S, Sanchez-Nino MD, Neria F, Goncalves S, Calabia O, Tejedor A, Calzada MJ, Caramelo C, Deudero JJ. et al.AG490 Promotes HIF-1alpha accumulation by inhibiting its hydroxylation. Curr Med Chem. 2012;19(23):4014–4023. doi: 10.2174/092986712802002554. PubMed DOI

Altun M, Zhao B, Velasco K, Liu H, Hassink G, Paschke J, Pereira T, Lindsten K. Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1α (HIF-1α) during hypoxia. J Biol Chem. 2012;287(3):1962–1969. doi: 10.1074/jbc.M111.305615. PubMed DOI PMC

Xu J, Wang B, Xu Y, Sun L, Tian W, Shukla D, Barod R, Grillari J, Grillari-Voglauer R, Maxwell PH. et al.Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element. Oncogene. 2012;31(8):1065–1072. doi: 10.1038/onc.2011.305. PubMed DOI

Dimova EY, Michiels C, Kietzmann T. Kinases as upstream regulators of the HIF system: their emerging potential as anti-cancer drug targets. Curr Pharm Des. 2009;15(33):3867–3877. doi: 10.2174/138161209789649358. PubMed DOI

Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R, Zat'ovicova M, Liao S, Portetelle D, Stanbridge EJ. et al.Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene. 1994;9(10):2877–2888. PubMed

Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH. et al.Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60(24):7075–7083. PubMed

Ditte P, Dequiedt F, Svastova E, Hulikova A, Ohradanova-Repic A, Zatovicova M, Csaderova L, Kopacek J, Supuran CT, Pastorekova S. et al.Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors. Cancer Res. 2011;71(24):7558–7567. doi: 10.1158/0008-5472.CAN-11-2520. PubMed DOI

Svastova E, Hulikova A, Rafajova M, Zat'ovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J. et al.Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. 2004;577(3):439–445. doi: 10.1016/j.febslet.2004.10.043. PubMed DOI

Chiche J, Ilc K, Brahimi-Horn MC, Pouyssegur J. Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration. Adv Enzyme Regul. 2010;50(1):20–33. doi: 10.1016/j.advenzreg.2009.10.005. PubMed DOI

Swietach P, Wigfield S, Cobden P, Supuran CT, Harris AL, Vaughan-Jones RD. Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. J Biol Chem. 2008;283(29):20473–20483. doi: 10.1074/jbc.M801330200. PubMed DOI

Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A, Zatovicova M, Barathova M, Kopacek J, Pastorek J. et al.Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem. 2012;287(5):3392–3402. doi: 10.1074/jbc.M111.286062. PubMed DOI PMC

Buchler P, Reber HA, Buchler M, Shrinkante S, Buchler MW, Friess H, Semenza GL, Hines OJ. Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas. 2003;26(1):56–64. doi: 10.1097/00006676-200301000-00010. PubMed DOI

Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604–4613. PubMed PMC

Wan J, Chai H, Yu Z, Ge W, Kang N, Xia W, Che Y. HIF-1α effects on angiogenic potential in human small cell lung carcinoma. J Exp Clin Cancer Res. 2011;30(1):77. doi: 10.1186/1756-9966-30-77. PubMed DOI PMC

Brahimi-Horn MC, Bellot G, Pouyssegur J. Hypoxia and energetic tumour metabolism. Curr Opin Genet Dev. 2011;21(1):67–72. doi: 10.1016/j.gde.2010.10.006. PubMed DOI

Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL, Simon MC, Thompson CB. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 2007;21(9):1037–1049. doi: 10.1101/gad.1529107. PubMed DOI PMC

Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11(5):407–420. doi: 10.1016/j.ccr.2007.04.001. PubMed DOI

Marin-Hernandez A, Gallardo-Perez JC, Ralph SJ, Rodriguez-Enriquez S, Moreno-Sanchez R. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem. 2009;9(9):1084–1101. doi: 10.2174/138955709788922610. PubMed DOI

Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–634. doi: 10.1038/onc.2009.441. PubMed DOI PMC

Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 2011;14(3):191–201. doi: 10.1016/j.drup.2011.03.001. PubMed DOI

Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9(5):402–412. doi: 10.1038/nrm2395. PubMed DOI

Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458(7242):1127–1130. doi: 10.1038/nature07986. PubMed DOI PMC

Feng Z, Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 2010;20(7):427–434. doi: 10.1016/j.tcb.2010.03.004. PubMed DOI PMC

Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. PubMed DOI

Prives C. Signaling to p53: breaking the MDM2-p53 circuit. Cell. 1998;95(1):5–8. doi: 10.1016/S0092-8674(00)81774-2. PubMed DOI

Chen L, Li Z, Zwolinska AK, Smith MA, Cross B, Koomen J, Yuan Z-M, Jenuwein T, Marine J-C, Wright KL. et al.MDM2 Recruitment of lysine methyltransferases regulates p53 transcriptional output. EMBO J. 2010;29(15):2538–2552. doi: 10.1038/emboj.2010.140. PubMed DOI PMC

Candeias MM, Malbert-Colas L, Powell DJ, Daskalogianni C, Maslon MM, Naski N, Bourougaa K, Calvo F, Fahraeus R. P53 MRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol. 2008;10(9):1098–1105. doi: 10.1038/ncb1770. PubMed DOI

Gajjar M, Candeias MM, Malbert-Colas L, Mazars A, Fujita J, Olivares-Illana V, Fahraeus R. The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA damage. Cancer Cell. 2012;21(1):25–35. doi: 10.1016/j.ccr.2011.11.016. PubMed DOI

Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA. 2005;102(23):8204–8209. doi: 10.1073/pnas.0502857102. PubMed DOI PMC

Sen N, Satija YK, Das S. p53 and metabolism: old player in a new game. Transcription. 2012;3(3):119–123. doi: 10.4161/trns.20094. PubMed DOI PMC

Hublarova P, Greplova K, Holcakova J, Vojtesek B, Hrstka R. Switching p53-dependent growth arrest to apoptosis via the inhibition of DNA damage-activated kinases. Cell Mol Biol Lett. 2010;15(3):473–484. doi: 10.2478/s11658-010-0021-5. PubMed DOI PMC

Chen BP, Wolfgang CD, Hai T. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol. 1996;16(3):1157–1168. PubMed PMC

Tanaka Y, Nakamura A, Morioka MS, Inoue S, Tamamori-Adachi M, Yamada K, Taketani K, Kawauchi J, Tanaka-Okamoto M, Miyoshi J. et al.Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway. PLoS One. 2011;6(10):e26848. doi: 10.1371/journal.pone.0026848. PubMed DOI PMC

Zhang X-P, Liu F, Wang W. Two-phase dynamics of p53 in the DNA damage response. Proc Natl Acad Sci USA. 2011;108(22):8990–8995. doi: 10.1073/pnas.1100600108. PubMed DOI PMC

Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H, Taya Y, Imai K. p53-Inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J. 2000;19(23):6517–6526. doi: 10.1093/emboj/19.23.6517. PubMed DOI PMC

Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M, Criollo A, Morselli E, Zhu C, Harper F. et al.Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008;10(6):676–687. doi: 10.1038/ncb1730. PubMed DOI PMC

Prives C, Hall PA. The p53 pathway. J Pathol. 1999;187(1):112–126. doi: 10.1002/(SICI)1096-9896(199901)187:1<112::AID-PATH250>3.0.CO;2-3. PubMed DOI

Muller P, Hrstka R, Coomber D, Lane DP, Vojtesek B. Chaperone-dependent stabilization and degradation of p53 mutants. Oncogene. 2008;27(24):3371–3383. doi: 10.1038/sj.onc.1211010. PubMed DOI

Royds JA, Dower SK, Qwarnstrom EE, Lewis CE. Response of tumour cells to hypoxia: role of p53 and NFkB. Mol Pathol. 1998;51(2):55–61. doi: 10.1136/mp.51.2.55. PubMed DOI PMC

Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ Jr, Giaccia AJ. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol. 1994;14(9):6264–6277. doi: 10.1128/MCB.14.9.6264. PubMed DOI PMC

Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ. Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol. 2002;22(6):1834–1843. doi: 10.1128/MCB.22.6.1834-1843.2002. PubMed DOI PMC

Hubert A, Paris S, Piret JP, Ninane N, Raes M, Michiels C. Casein kinase 2 inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated p53 protein level. J Cell Sci. 2006;119(Pt 16):3351–3362. PubMed

Zhang L, Hill RP. Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res. 2004;64(12):4180–4189. doi: 10.1158/0008-5472.CAN-03-3038. PubMed DOI

Wouters A, Pauwels B, Lambrechts HAJ, Pattyn GGO, Ides J, Baay M, Meijnders P, Dewilde S, Vermorken JB, Lardon F. Chemoradiation interactions under reduced oxygen conditions: cellular characteristics of an in vitro model. Cancer Lett. 2009;286(2):180–188. doi: 10.1016/j.canlet.2009.05.026. PubMed DOI

Sermeus A, Michiels C. Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2011;2:e164. doi: 10.1038/cddis.2011.48. PubMed DOI PMC

Suzuki H, Tomida A, Tsuruo T. Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene. 2001;20(41):5779–5788. doi: 10.1038/sj.onc.1204742. PubMed DOI

An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature. 1998;392(6674):405–408. doi: 10.1038/32925. PubMed DOI

Achison M, Hupp TR. Hypoxia attenuates the p53 response to cellular damage. Oncogene. 2003;22(22):3431–3440. doi: 10.1038/sj.onc.1206434. PubMed DOI

Cosse J-P, Sermeus A, Vannuvel K, Ninane N, Raes M, Michiels C. Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines. Mol Cancer. 2007;6:61. PubMed PMC

Kaluzova M, Kaluz S, Lerman MI, Stanbridge EJ. DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol Cell Biol. 2004;24(13):5757–5766. doi: 10.1128/MCB.24.13.5757-5766.2004. PubMed DOI PMC

Nardinocchi L, Puca R, D'Orazi G. HIF-1 alpha antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging-Us. 2011;3(1):33–43. PubMed PMC

D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G. et al.Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol. 2002;4(1):11–19. doi: 10.1038/ncb714. PubMed DOI

Nardinocchi L, Puca R, Sacchi A, Rechavi G, Givol D, D'Orazi G. Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF-1 alpha. PLoS One. 2009;4(8):e6819. doi: 10.1371/journal.pone.0006819. PubMed DOI PMC

Gogna R, Madan E, Kuppusamy P, Pati U. Chaperoning of mutant p53 protein by wild-type p53 protein causes hypoxic tumor regression. J Biol Chem. 2012;287(4):2907–2914. doi: 10.1074/jbc.M111.317354. PubMed DOI PMC

Madan E, Gogna R, Pati U. p53 Ser15 Phosphorylation disrupts the p53-RPA70 complex and induces RPA70-mediated DNA repair in hypoxia. Biochem J. 2012;443(3):811–820. doi: 10.1042/BJ20111627. PubMed DOI

Thomas DD, Espey MG, Ridnour LA, Hofseth LJ, Mancardi D, Harris CC, Wink DA. Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc Natl Acad Sci USA. 2004;101(24):8894–8899. doi: 10.1073/pnas.0400453101. PubMed DOI PMC

Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–314. doi: 10.1126/science.123.3191.309. PubMed DOI

Yalcin A, Telang S, Clem B, Chesney J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol. 2009;86(3):174–179. doi: 10.1016/j.yexmp.2009.01.003. PubMed DOI

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–1033. doi: 10.1126/science.1160809. PubMed DOI PMC

Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–707. doi: 10.1016/j.cell.2008.08.021. PubMed DOI

Ferguson EC, Rathmell JC. New roles for pyruvate kinase M2: working out the Warburg effect. Trends Biochem Sci. 2008;33(8):359–362. doi: 10.1016/j.tibs.2008.05.006. PubMed DOI PMC

Hommes FA, Everts RS. Particulate and free hexokinase in fetal rat liver. Biol Neonate. 1978;33(3–4):193–200. PubMed

Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition. 2000;16(3):202–208. doi: 10.1016/S0899-9007(99)00266-X. PubMed DOI

Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, Ushijima M, Mashima T, Seimiya H, Satoh Y. et al.ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008;68(20):8547–8554. doi: 10.1158/0008-5472.CAN-08-1235. PubMed DOI

Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ. et al.IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. doi: 10.1056/NEJMoa0808710. PubMed DOI PMC

Young CD, Anderson SM. Sugar and fat - that's where it's at: metabolic changes in tumors. Breast Cancer Res. 2008;10(1):202. doi: 10.1186/bcr1852. PubMed DOI PMC

Mentis A-FA, Kararizou E. Metabolism and cancer: an up-to-date review of a mutual connection. Asian Pac J Cancer Prev. 2010;11(6):1437–1444. PubMed

Israel M, Schwartz L. The metabolic advantage of tumor cells. Mol Cancer. 2011;10:70. doi: 10.1186/1476-4598-10-70. PubMed DOI PMC

Munoz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 2012;3:e248. doi: 10.1038/cddis.2011.123. PubMed DOI PMC

Guccini I, Serio D, Condo I, Rufini A, Tomassini B, Mangiola A, Maira G, Anile C, Fina D, Pallone F. et al.Frataxin participates to the hypoxia-induced response in tumors. Cell Death Dis. 2011;2:e123. doi: 10.1038/cddis.2011.5. PubMed DOI PMC

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85. doi: 10.1016/j.ccr.2004.11.022. PubMed DOI

Kawauchi K, Araki K, Tobiume K, Tanaka N. p53 Regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol. 2008;10(5):611–618. doi: 10.1038/ncb1724. PubMed DOI

Wanka C, Brucker DP, B√§hr O, Ronellenfitsch M, Weller M, Steinbach JP, Rieger J. Synthesis of cytochrome c oxidase 2: a p53-dependent metabolic regulator that promotes respiratory function and protects glioma and colon cancer cells from hypoxia-induced cell death. Oncogene. 2012;31(33):3764–3776. doi: 10.1038/onc.2011.530. PubMed DOI

White E, Karp C, Strohecker AM, Guo YX, Mathew R. Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol. 2010;22(2):212–217. doi: 10.1016/j.ceb.2009.12.008. PubMed DOI PMC

Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol. 2010;22(2):177–180. doi: 10.1016/j.ceb.2009.11.015. PubMed DOI

Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang CW, Pavlides S, Martinez-Cantarin MP, Capozza F. et al.Autophagy in cancer associated fibroblasts promotes tumor cell survival role of hypoxia, HIF1 induction and NF kappa B activation in the tumor stromal microenvironment. Cell Cycle. 2010;9(17):3515–3533. doi: 10.4161/cc.9.17.12928. PubMed DOI PMC

Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126(1):121–134. doi: 10.1016/j.cell.2006.05.034. PubMed DOI

Xu-Monette ZY, Young KH. The TP53 tumor suppressor and autophagy in malignant lymphoma. Autophagy. 2012;8(5):842–845. doi: 10.4161/auto.19703. PubMed DOI PMC

Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T. et al.Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25(3):1025–1040. doi: 10.1128/MCB.25.3.1025-1040.2005. PubMed DOI PMC

Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M, Criollo A, Morselli E, Zhu CL, Harper F. et al.Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008;10(6):676–687. doi: 10.1038/ncb1730. PubMed DOI PMC

Naves T, Jawhari S, Jauberteau MO, Ratinaud MH, Verdier M. Autophagy takes place in mutated p53 neuroblastoma cells in response to hypoxia mimetic CoCl2. Biochem Pharmacol. 2013;85(8):1153–1161. doi: 10.1016/j.bcp.2013.01.022. PubMed DOI

Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV. Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc Natl Acad Sci USA. 2012;109(33):13314–13318. doi: 10.1073/pnas.1205690109. PubMed DOI PMC

Dos Santos F, Andrade PZ, Boura JS, Abecasis MM, da Silva CL, Cabral JM. Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. J Cell Physiol. 2010;223(1):27–35. PubMed

Tsai CC, Chen YJ, Yew TL, Chen LL, Wang JY, Chiu CH, Hung SC. Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. Blood. 2011;117(2):459–469. doi: 10.1182/blood-2010-05-287508. PubMed DOI

Welford SM, Giaccia AJ. Hypoxia and senescence: the impact of oxygenation on tumor suppression. Mol Cancer Res. 2011;9(5):538–544. doi: 10.1158/1541-7786.MCR-11-0065. PubMed DOI PMC

Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci USA. 1995;92(10):4337–4341. doi: 10.1073/pnas.92.10.4337. PubMed DOI PMC

Capparelli C, Whitaker-Menezes D, Guido C, Balliet R, Pestell TG, Howell A, Sneddon S, Pestell RG, Martinez-Outschoorn U, Lisanti MP. et al.CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle. 2012;11(12):2272–2284. doi: 10.4161/cc.20717. PubMed DOI PMC

Welford SM, Dorie MJ, Li X, Haase VH, Giaccia AJ. Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol Cell Biol. 2010;30(19):4595–4603. doi: 10.1128/MCB.01618-09. PubMed DOI PMC

Dulic V. Senescence regulation by mTOR. Methods Mol Biol. 2013;965:15–35. doi: 10.1007/978-1-62703-239-1_2. PubMed DOI

Hasty P, Sharp ZD, Curiel TJ, Campisi J. mTORC1 and p53: clash of the gods? Cell Cycle. 2013;12(1):20–25. doi: 10.4161/cc.22912. PubMed DOI PMC

Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013. Epub ahead of print. PubMed DOI

Blagosklonny MV. Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression? Aging. 2012;4(7):450–455. PubMed PMC

Ousset M, Bouquet F, Fallone F, Biard D, Dray C, Valet P, Salles B, Muller C. Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: role in the physiopathology of the disease. Cell Cycle. 2010;9(14):2814–2822. doi: 10.4161/cc.9.14.12253. PubMed DOI

Cam H, Easton JB, High A, Houghton PJ. mTORC1 Signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell. 2010;40(4):509–520. doi: 10.1016/j.molcel.2010.10.030. PubMed DOI PMC

Freedman SJ, Sun Z-YJ, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha. Proc Natl Acad Sci U S A. 2002;99(8):5367–5372. doi: 10.1073/pnas.082117899. PubMed DOI PMC

Xenaki G, Ontikatze T, Rajendran R, Stratford IJ, Dive C, Krstic-Demonacos M, Demonacos C. PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene. 2008;27(44):5785–5796. doi: 10.1038/onc.2008.192. PubMed DOI PMC

Roe JS, Kim H, Lee SM, Kim ST, Cho EJ, Youn HD. p53 Stabilization and transactivation by a von hippel-lindau protein. Mol Cell. 2006;22(3):395–405. doi: 10.1016/j.molcel.2006.04.006. PubMed DOI

Pelletier J, Dayan F, Durivault J, Ilc K, Pecou E, Pouyssegur J, Mazure NM. The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53-p21 axis. Oncogene. 2012;31(24):2989–3001. doi: 10.1038/onc.2011.471. PubMed DOI

Ashcroft M, Taya Y, Vousden KH. Stress signals utilize multiple pathways to stabilize p53. Mol Cell Biol. 2000;20(9):3224–3233. doi: 10.1128/MCB.20.9.3224-3233.2000. PubMed DOI PMC

Koumenis C, Alarcon R, Hammond E, Sutphin P, Hoffman W, Murphy M, Derr J, Taya Y, Lowe SW, Kastan M. et al.Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol Cell Biol. 2001;21(4):1297–1310. doi: 10.1128/MCB.21.4.1297-1310.2001. PubMed DOI PMC

Koshikawa N, Maejima C, Miyazaki K, Nakagawara A, Takenaga K. Hypoxia selects for high-metastatic Lewis lung carcinoma cells overexpressing Mcl-1 and exhibiting reduced apoptotic potential in solid tumors. Oncogene. 2006;25(6):917–928. doi: 10.1038/sj.onc.1209128. PubMed DOI

Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56(19):4509–4515. PubMed

Cleven AHG, van Engeland M, Wouters BG, de Bruine AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol. 2007;29(3):229–240. PubMed PMC

Cleven AH, Wouters BG, Schutte B, Spiertz AJ, van Engeland M, de Bruine AP. Poorer outcome in stromal HIF-2 alpha- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis. Br J Cancer. 2008;99(5):727–733. doi: 10.1038/sj.bjc.6604547. PubMed DOI PMC

O'Toole D, Couvelard A, Rebours V, Zappa M, Hentic O, Hammel P, Levy P, Bedossa P, Raymond E, Ruszniewski P. Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17(4):847–856. doi: 10.1677/ERC-09-0204. PubMed DOI

Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, Candiloro I, Pezzella F, Gatter KC, Millar EK. et al.The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer. 2009;100(2):405–411. doi: 10.1038/sj.bjc.6604844. PubMed DOI PMC

Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996;77(5):858–863. doi: 10.1002/(SICI)1097-0142(19960301)77:5<858::AID-CNCR8>3.0.CO;2-A. PubMed DOI

Andersen S, Donnem T, Stenvold H, Al-Saad S, Al-Shibli K, Busund L-T, Bremnes RM. Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PLoS One. 2011;6(8):e23847. doi: 10.1371/journal.pone.0023847. PubMed DOI PMC

Henze A-T, Riedel J, Diem T, Wenner J, Flamme I, Pouyseggur J, Plate KH, Acker T. Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. Cancer Res. 2010;70(1):357–366. doi: 10.1158/0008-5472.CAN-09-1876. PubMed DOI

Baas IO, Hruban RH, Offerhaus GJ. Clinical applications of detecting dysfunctional p53 tumor suppressor protein. Histol Histopathol. 1999;14(1):279–284. PubMed

Khromova NV, Kopnin PB, Stepanova EV, Agapova LS, Kopnin BP. p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-a pathway. Cancer Lett. 2009;276(2):143–151. doi: 10.1016/j.canlet.2008.10.049. PubMed DOI

Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, Chung DC, Giovannucci EL, Fuchs CS, Ogino S. HIF1A Overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol. 2010;176(5):2292–2301. doi: 10.2353/ajpath.2010.090972. PubMed DOI PMC

Fondevila C, Metges JP, Fuster J, Grau JJ, Palacín A, Castells A, Volant A, Pera M. p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer. 2004;90(1):206–215. doi: 10.1038/sj.bjc.6601455. PubMed DOI PMC

Oh SY, Kwon H-C, Kim S-H, Jang JS, Kim MC, Kim KH, Han J-Y, Kim CO, Kim S-J, Jeong J-s. et al.Clinicopathologic significance of HIF-1alpha, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer. BMC Cancer. 2008;8:123. doi: 10.1186/1471-2407-8-123. PubMed DOI PMC

Gryko M, Pryczynicz A, Guzinska-Ustymowicz K, Kamocki Z, Zareba K, Kemona A, Kedra B. Immunohistochemical assessment of apoptosis-associated proteins: p53, Bcl-xL, Bax and Bak in gastric cancer cells in correlation with clinical and pathomorphological factors. Adv Med Sci. 2012;57(1):77–83. PubMed

Wang J, Biju MP, Wang M-H, Haase VH, Dong Z. Cytoprotective effects of hypoxia against cisplatin-induced tubular cell apoptosis: involvement of mitochondrial inhibition and p53 suppression. J Am Soc Nephrol. 2006;17(7):1875–1885. doi: 10.1681/ASN.2005121371. PubMed DOI

Brown JM. Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol Med Today. 2000;6(4):157–162. doi: 10.1016/S1357-4310(00)01677-4. PubMed DOI

Fardel O, Lecureur V, Guillouzo A. The P-glycoprotein multidrug transporter. Gen Pharmacol. 1996;27(8):1283–1291. doi: 10.1016/S0306-3623(96)00081-X. PubMed DOI

Tiwari AK, Sodani K, Dai C-L, Ashby CR Jr, Chen Z-S. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011;12(4):570–594. doi: 10.2174/138920111795164048. PubMed DOI

Doublier S, Belisario DC, Polimeni M, Annaratone L, Riganti C, Allia E, Ghigo D, Bosia A, Sapino A. HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast. BMC Cancer. 2012;12:4. doi: 10.1186/1471-2407-12-4. PubMed DOI PMC

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?