Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

Abstract

Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization.

Keywords: autophagy; chemoresistance; p53.

Figure 1

Gain of function (GOF) effect of mutant p53 and regulation of autophagy by p53 in nucleus. Certain p53 mutations (such as R248Q, R273H, R175H, and R249S) have shown GOF can further promote cancer malignance and chemoresistance. p53 mutants are able to actuate various survival signaling cascades, such as the NF-κB, PDGFRβ, mevalonate, proteasomal, or integrin pathways, and activate an independent set of target genes in cooperation with other transcription factors or cofactors (such as Pin1 and PML proteins). Nuclear p53 localization can promote autophagy by regulating the mTOR pathway in a transcription-dependent manner. Some p53 targeted genes, including PTEN, TSC2, and AMPKβ, have been reported to negatively regulate mTOR, thus promoting autophagy initiation. In addition, p53 can also be associated with autophagy through the ARF-signaling pathway. Regulation between p53 and the different functional forms of autophagy can contribute to chemotherapy resistance in tumor cells.