p53-Dependent Cytoprotective Mechanisms behind Resistance to Chemo-Radiotherapeutic Agents Used in Cancer Treatment

Abstract

Resistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early response gene 5 (IER5)/heat-shock factor 1 (HSF1) pathway, and p21/nuclear factor erythroid 2–related factor 2 (NRF2) pathway, which are regulated by the tumour suppressor p53. Upon DNA damage caused during chemoradiotherapy, p53 is recruited to the sites of DNA damage and activates various DNA repair enzymes including GADD45A, p53R2, DDB2 to repair damaged-DNA in cancer cells. In addition, the p53-IER5-HSF1 pathway protects cancer cells from proteomic stress and maintains cellular proteostasis. Further, the p53-p21-NRF2 pathway induces production of antioxidants and multidrug resistance-associated proteins to protect cancer cells from therapy-induced oxidative stress and to promote effusion of drugs from the cells. This review summarises possible roles of these p53-regulated cytoprotective mechanisms in the resistance to chemoradiotherapy.

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“…The p53 protein is an important tumor suppressor and a transcription factor that regulates a huge number of genes depending on cellular conditions. Since it is a common gene that is mutated in the majority of cancers, this protein is called "the guardian of cells or genome" [33]. When DNA damage occurs, the TP53 gene (the gene that encodes the p53 protein) stops the cell cycle, and if the p53 protein is mutated, the cell cycle becomes unconstrained and the damaged DNA is replicated, resulting in uncontrolled cell proliferation and cancer tumors [34].…”