The role of p53 in chemosensitivity and radiosensitivity

El‐Deiry, Wafik S.

doi:10.1038/sj.onc.1206949

Cited by 310 publications

(256 citation statements)

References 99 publications

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“…14 While the killing of cancer cells by p53 does not require a fully functional immune system, p53 can push cancer cells toward apoptotic death and tends to sensitize tumors to conventional therapeutic modalities (chemotherapy and radiotherapy) that result in DNA damage. 26 Indeed, we have shown that the restoration of p53 function via SGT-53, a tumor-targeted nanomedicine, could inhibit tumor growth and sensitize xenografts of human tumors in nude mice lacking T cells to both chemotherapy 27,28 and radiotherapy. 29 Nonetheless, it has become clear that p53 also participates in various aspects of immune modulation in cancer.…”

Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…Among the numerous factors that exert the cellular stress responses, the tumor suppressor p53 plays a pivotal role. P53 becomes activated by several stress stimuli, for example, UV-and gamma-irradiation, nucleotide depletion, hypoxia and diverse chemotherapeutic agents (El-Deiry, 2003). Hallmarks of p53 activation are stabilization of the p53 protein, its accumulation in the nucleus and its modification, for example, phosphorylation by the ATM and ATR kinases at serine 15 in human, and serine 18 in mouse p53 (El-Deiry, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…P53 becomes activated by several stress stimuli, for example, UV-and gamma-irradiation, nucleotide depletion, hypoxia and diverse chemotherapeutic agents (El-Deiry, 2003). Hallmarks of p53 activation are stabilization of the p53 protein, its accumulation in the nucleus and its modification, for example, phosphorylation by the ATM and ATR kinases at serine 15 in human, and serine 18 in mouse p53 (El-Deiry, 2003). Activated p53 is capable of triggering the induction of three different types of cellular stress responses: (i) transient cell cycle arrest, accompanied by DNA-repair; (ii) terminal growth arrest, which is associated with a senescence-like phenotype and permanently excludes cells from further divisions; (iii) activation of the apoptotic program.…”

Section: Introductionmentioning

confidence: 99%

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Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress

2005

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Following genotoxic stress, p53 either rescues a damaged cell or promotes its elimination. The parameters determining a specific outcome of the p53 response are largely unknown. In mouse fibroblasts treated with different irradiation schemes, we monitored transcriptional and non-transcriptional p53 activities and identified determinants that initiate an anti-or a pro-apoptotic p53 response within the context of p53-independent stress signaling. The primary, transcription-mediated p53 response in these cells is anti-apoptotic, while induction of p53-dependent apoptosis requires an additional, transcription-independent p53 activity, provided by high intracellular levels of activated p53. High intracellular levels of p53 were selectively generated after apoptosis-inducing high-dose UV-irradiation, and correlated with a strongly delayed upregulation of Mdm2. Following high-dose UV-irradiation, p53 accumulated in the cytoplasm and led to activation of the pro-apoptotic protein Bax. As p53-dependent Bax-activation is transcription-independent, we postulated that certain transcription-deficient mutant p53 proteins might also exert this activity. Indeed we found an endogenous, transcription-inactive mutant p53 that upon genotoxic stress induced Bax-activation in vivo. Our results demonstrate the impact and in vivo relevance of non-transcriptional mechanisms for wild-type and mutant p53-mediated apoptosis. Oncogene (2006) 25, 940-953.

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“…One of the major cellular responses to DNA damage inflicted by cisplatin and related cellular stresses in a variety of cells involves upregulation of p53 protein, which is usually undetectable in normal cells. 5,6 Upon activation, p53 binds to specific DNA sequences that promote transcription of target genes, including genes associated with apoptosis and cell cycle arrest, [6][7][8][9] in a tissue-and cell-specific manner. 10,11 Upon receiving a proapoptotic stimulus, most if not all of the signaling pathways of cell death converge into the activation of executioner caspase-3, -6, and -7.…”

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confidence: 99%

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

et al. 2007

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This study examined the role of cisplatin-induced p53 activation in regulation of caspases and cellular injury during cisplatin nephrotoxicity. The executioner caspase-6 and -7 but not caspase-3 were identified as transcriptional targets of p53 in cisplatin injury as revealed by chromatin immunoprecipitation, a reporter gene and electrophoretic mobility shift assays, and real-time PCR following overexpression and inhibition of p53. DNA binding by p53 involved the first introns of the human and mouse caspase-7 gene and the mouse caspase-6 gene. Studies in human kidney, breast, ovary, colon, and prostate tumor cell lines also validated these findings. Treatment of p53 (À/À) cells with cisplatin did not induce caspase-6 and -7 expression and subsequent activation. In caspase-3 (À/À) cells, inhibition of caspase-6 and -7 activations markedly prevented cisplatin-induced cell death.In an in vivo model of cisplatin nephrotoxicity inhibition of p53 activation by a p53 inhibitor suppressed transactivation of the caspase-6 and -7 genes and prevented renal failure. p53 (À/À) mice were resistant to cisplatin nephrotoxicity as assessed by renal function and histology. These studies provide first evidence for p53-dependent transcriptional control of the caspase-6 and -7 genes and its functional significance in cisplatin injury to renal cells and functional implication of cisplatin-induced p53 induction in vitro and in vivo in cisplatin nephrotoxicity.

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The role of p53 in chemosensitivity and radiosensitivity

Cited by 310 publications

References 99 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

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