Abstract
DNA damage induced by reactive oxygen species and several chemotherapeutic agents promotes both p53 and poly (ADP-ribose) polymerase (PARP) activation. p53 activation is well known to regulate apoptotic cell death, whereas robust activation of PARP-1 has been shown to promote a necrotic cell death associated with energetic collapse. Here we identify a novel role for p53 in modulating PARP enzymatic activity to regulate necrotic cell death. In mouse embryonic fibroblasts, human colorectal and human breast cancer cell lines, loss of p53 function promotes resistance to necrotic, PARP-mediated cell death. We therefore demonstrate that p53 can regulate both necrotic and apoptotic cell death, mutations or deletions in this tumor-suppressor protein may be selected by cancer cells to provide not only their resistance to apoptosis but also to necrosis, and explain resistance to chemotherapy and radiation even when it kills via non-apoptotic mechanisms.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- 4-ANI:
-
4-amino-1,8-naphthalimide
- ADP:
-
adenosine diphosphate
- BH3:
-
Bcl-2 homology domain 3
- CHAPS:
-
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate
- DD:
-
dominant negative
- DKO:
-
double knockout
- FACS:
-
fluorescence-activated cell sorting
- H2O2:
-
hydrogen peroxide
- KD:
-
knockdown
- KO:
-
knockout
- MEF:
-
mouse embryonic fibroblast
- MOMP:
-
mitochondrial outer membrane permeabilization
- NAD:
-
nicotinamide adenine dinucleotide
- PARG:
-
poly (ADP-ribose) glycohydrolase
- PARP:
-
poly (ADP-ribose) polymerase
- PBS:
-
phosphate-buffered saline
- ROS:
-
reactive oxygen species
- ShRNA:
-
short hairpin RNA
References
Ikediobi ON, Davies H, Bignell G, Edkins S, Stevens C, O'Meara S et al. Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol Cancer Ther 2006; 5: 2606–2612.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 2012; 483: 603–607.
Greenblatt MS, Bennett WP, Hollstein M, Harris CC . Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer research 1994; 54: 4855–4878.
Riley T, Sontag E, Chen P, Levine A . Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 2008; 9: 402–412.
Chipuk JE, Green DR . Dissecting p53-dependent apoptosis. Cell death and differentiation 2006; 13: 994–1002.
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science (New York, N.Y 2004; 303: 1010–1014.
Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW . Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 2002; 1: 289–298.
Villunger A, Michalak EM, Coultas L, Müllauer F, Böck G, Ausserlechner MJ et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science (New York) NY 2003; 302: 1036–1038.
Macip S, Kosoy A, Lee SW, O'Connell MJ, Aaronson SA . Oxidative stress induces a prolonged but reversible arrest in p53-null cancer cells, involving a Chk1-dependent G2 checkpoint. Oncogene 2006; 25: 6037–6047.
Schreiber V, Dantzer F, Ame JC, de Murcia G . Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 2006; 7: 517–528.
Chang P, Jacobson MK, Mitchison TJ . Poly(ADP-ribose) is required for spindle assembly and structure. Nature 2004; 432: 645–649.
Yelamos J, Farres J, Llacuna L, Ampurdanes C, Martin-Caballero J . PARP-1 and PARP-2: New players in tumour development. Am J Cancer Res 2011; 1: 328–346.
Leung M, Rosen D, Fields S, Cesano A, Budman DR . Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality. Mol Med (Cambridge) Mass 2011; 17: 854–862.
Munoz-Gamez JA, MartÃn-Oliva D, Aguilar-Quesada R, Cañuelo A, Nuñez MI, Valenzuela MT et al. PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. Biochem J 2005; 386: 119–125.
Malanga M, Althaus FR . The role of poly(ADP-ribose) in the DNA damage signaling network. Biochem Cell Biol 2005; 83: 354–364.
Kumari SR, Mendoza-Alvarez H, Alvarez-Gonzalez R . Functional interactions of p53 with poly(ADP-ribose) polymerase (PARP) during apoptosis following DNA damage: covalent poly(ADP-ribosyl)ation of p53 by exogenous PARP and noncovalent binding of p53 to the M(r) 85,000 proteolytic fragment. Cancer Res 1998; 58: 5075–5078.
Valenzuela MT, Guerrero R, Núñez MI, Ruiz De Almodóvar JM, Sarker M, de Murcia G et al. PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene 2002; 21: 1108–1116.
Alvarez-Gonzalez R . Genomic maintenance: the p53 poly(ADP-ribosyl)ation connection. Sci STKE 2007; 2007: pe68.
David KK, Andrabi SA, Dawson TM, Dawson VL . Parthanatos, a messenger of death. Front Biosci 2009; 14: 1116–1128.
Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB . Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 2004; 18: 1272–1282.
Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science (New York) NY 2002; 297: 259–263.
Moubarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier-de Murcia J et al. Sequential activation of poly(ADP-ribose) polymerase 1, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 2007; 27: 4844–4862.
Blenn C, Wyrsch P, Bader J, Bollhalder M, Althaus FR . Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death. Cell Mol Life Sci 2011; 68: 1455–1466.
Ha HC, Snyder SH . Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 1999; 96: 13978–13982.
Zong WX, Thompson CB . Necrotic death as a cell fate. Genes Dev 2006; 20: 1–15.
Tong WM, Hande MP, Lansdorp PM, Wang ZQ . DNA strand break-sensing molecule poly(ADP-Ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression. Mol Cell Biol 2001; 21: 4046–4054.
Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB . BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 2001; 15: 1481–1486.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH . Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 2000; 7: 1166–1173.
Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM . p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 2012; 149: 1536–1548.
Vanden Berghe T, Grootjans S, Goossens V, Dondelinger Y, Krysko DV, Takahashi N et al. Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods 2013; S1046-2023(13)00030-3.
Eguchi Y, Shimizu S, Tsujimoto Y . Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997; 57: 1835–1840.
Ryan JA, Brunelle JK, Letai A . Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proc Natl Acad Sci USA 2010; 107: 12895–12900.
Chonghaile TN, Letai A . Who put the ‘A’ in Atg12: autophagy or apoptosis? Mol Cell 2011; 44: 844–845.
Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science (New York) NY 2011; 334: 1129–1133.
Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE et al. p53 status and the efficacy of cancer therapy in vivo. Science (New York) NY 1994; 266: 807–810.
Tu HC, Ren D, Wang GX, Chen DY, Westergard TD, Kim H et al. The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage. Proc Natl Acad Sci USA 2009; 106: 1093–1098.
Mani M, Carrasco DE, Zhang Y, Takada K, Gatt ME, Dutta-Simmons J et al. BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. Cancer Res 2009; 69: 7577–7586.
Gottlieb E, Haffner R, von Ruden T, Wagner EF, Oren M . Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J 1994; 13: 1368–1374.
Lowe SW, Ruley HE, Jacks T, Housman DE . p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74: 957–967.
Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol Cell Biol 2009; 29: 4116–4129.
Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 1994; 78: 703–711.
Dutta C, Day T, Kopp N, van Bodegom D, Davids MS, Ryan J et al. BCL2 suppresses PARP1 function and nonapoptotic cell death. Cancer Res 2012; 72: 4193–4203.
Brumatti G, Sheridan C, Martin SJ . Expression and purification of recombinant annexin V for the detection of membrane alterations on apoptotic cells. Methods 2008; 44: 235–240.
Acknowledgements
We gratefully acknowledge funding from the Beatriu de Pinós program from la Generalitat de Catalunya in Spain (JM) and NIH grant P01CA139980. AL is a Leukemia and Lymphoma Society Scholar. We thank Dr. James DeCarpio’s lab, Dr. Ruben Carrasco’s lab, Nadja Kopp and Jeremy Ryan for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by M Oren
Supplementary Information accompanies this paper on Cell Death and Differentiation website
Supplementary information
Rights and permissions
About this article
Cite this article
Montero, J., Dutta, C., van Bodegom, D. et al. p53 regulates a non-apoptotic death induced by ROS. Cell Death Differ 20, 1465–1474 (2013). https://doi.org/10.1038/cdd.2013.52
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cdd.2013.52
Keywords
This article is cited by
-
Comparison of the effects of oxidative and inflammatory stresses on rat chondrocyte senescence
Scientific Reports (2023)
-
Combined inhibition of BADSer99 phosphorylation and PARP ablates models of recurrent ovarian carcinoma
Communications Medicine (2022)
-
Derepression of the USP22-FASN axis by p53 loss under oxidative stress drives lipogenesis and tumorigenesis
Cell Death Discovery (2022)
-
Nrf2 signaling activation by a small molecule activator compound 16 inhibits hydrogen peroxide-induced oxidative injury and death in osteoblasts
Cell Death Discovery (2022)
-
Unfolded protein response in colorectal cancer
Cell & Bioscience (2021)
