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p53 Signaling and Cancer Cell Response to Genotoxic Stress: Beyond Cell Cycle Checkpoints and Apoptosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 12420

Special Issue Editor

Special Issue Information

Dear Colleagues,

The landscape of the DNA damage response has changed. Notably, the biological outputs orchestrated by the p53 tumor suppressor extends far beyond conventional cell cycle arrest and/or apoptosis. Under physiological conditions (e.g., the absence of ectopic p53 gene expression), the activation of the p53 signaling pathway following exposure to ionizing radiation and chemotherapeutic agents serves to prevent death through apoptosis and other modes of cell death, and to induce a senescence-like proliferation arrest. The latter cells exhibit a highly enlarged morphology, remain dormant, secrete a myriad of growth promoting factors, and have the potential of giving rise to tumor repopulating progeny. Furthermore, cancer cells exhibiting apoptotic features following exposure to genotoxic agents can undergo a reversal process (anastasis), ultimately resulting in tumor re-population.

The purpose of this Special Issue is to bring together research/review articles on the growing complexity surrounding p53 in general, and the long-term biological outputs controlled by p53 and its key downstream effectors (e.g., CDKN1A) in particular. Articles on tumor heterogeneity, advances in single-cell detection methodologies to study cancer cell responses to genotoxic stress, and novel therapeutic approaches by targeting proliferation-arrested (dormant) cancer cells are particularly welcomed.

Prof. Dr. Razmik Mirzayans
Guest Editor

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Keywords

  • wild-type p53 signaling
  • mutant p53 signaling
  • cell cycle checkpoints
  • apoptosis
  • anastasis (apoptosis reversal)
  • therapy-induced senescence
  • tumor heterogeneity

Published Papers (2 papers)

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Research

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16 pages, 2917 KiB  
Article
Loss of p53 Sensitizes Cells to Palmitic Acid-Induced Apoptosis by Reactive Oxygen Species Accumulation
by Guowu Yu, Hongwei Luo, Na Zhang, Yongbin Wang, Yangping Li, Huanhuan Huang, Yinghong Liu, Yufeng Hu, Hanmei Liu, Junjie Zhang, Yi Tang and Yubi Huang
Int. J. Mol. Sci. 2019, 20(24), 6268; https://doi.org/10.3390/ijms20246268 - 12 Dec 2019
Cited by 41 | Viewed by 7446
Abstract
Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic β-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead [...] Read more.
Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic β-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead to cell cycle arrest, DNA repair, senescence, or apoptosis, depending on the severity/type of stress. Nonetheless, the precise role of p53 in lipotoxicity induced by palmitic acid is not clear. Here, our results show that palmitic acid induces p53 activation in a dose- and time-dependent manner. Furthermore, loss of p53 makes cells sensitive to palmitic acid-induced apoptosis. These results were demonstrated in human colon carcinoma cells (HCT116) and primary mouse embryo fibroblasts (MEF) through analysis of DNA fragmentation, flow cytometry, colony formation, and Western blots. In the HCT116 p53−/− cell line, palmitic acid induced greater reactive oxygen species formation compared to the p53+/+ cell line. The reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and reduced glutathione (GSH) partially attenuated apoptosis in the HCT116 p53−/− cell line but had no obvious effect on the p53+/+ cell line. Furthermore, p53 induced the expression of its downstream target genes, p21 and Sesn2, in response to ROS induced by palmitic acid. Loss of p21 also leads to more palmitic acid-induced cell apoptosis in the HCT116 cell line compared with HCT116 p53+/+ and HCT116 p53−/−. In a mouse model of obesity, glucose tolerance test assays showed higher glucose levels in p53−/− mice that received a high fat diet compared to wild type mice that received the same diet. There were no obvious differences between p53−/− and p53+/+ mice that received a regular diet. We conclude that p53 may provide some protection against palmitic acid- induced apoptosis in cells by targeting its downstream genes in response to this stress. Full article
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Review

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24 pages, 2632 KiB  
Review
Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy
by David Murray and Razmik Mirzayans
Int. J. Mol. Sci. 2020, 21(16), 5766; https://doi.org/10.3390/ijms21165766 - 11 Aug 2020
Cited by 23 | Viewed by 3670
Abstract
Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in [...] Read more.
Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence. Full article
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