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Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression

1
Department of Medical Sciences, University ‘G. d’Annunzio’, 66013 Chieti, Italy
2
Department of Research, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
3
Department of Experimental Medicine, “Sapienza” University of Rome, 00185 Rome, Italy
4
Laboratory Affiliated to Pasteur Institute, Italy-Foundation Cenci Bolognetti, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(5), 614; https://doi.org/10.3390/cancers11050614
Received: 16 April 2019 / Revised: 27 April 2019 / Accepted: 1 May 2019 / Published: 2 May 2019
(This article belongs to the Special Issue Targeting Solid Tumors)
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Abstract

The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies. View Full-Text
Keywords: mutant p53 (mutp53); gain-of-function (GOF); autophagy; endoplasmic reticulum (ER) stress; unfolded protein response (UPR); antioxidant response; heat shock protein (HSP); nuclear factor erythroid 2-related factor 2 (NRF2); hypoxia-inducible factor 1 (HIF-1); anticancer therapy mutant p53 (mutp53); gain-of-function (GOF); autophagy; endoplasmic reticulum (ER) stress; unfolded protein response (UPR); antioxidant response; heat shock protein (HSP); nuclear factor erythroid 2-related factor 2 (NRF2); hypoxia-inducible factor 1 (HIF-1); anticancer therapy
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D’Orazi, G.; Cirone, M. Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression. Cancers 2019, 11, 614.

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