School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Massey Cancer Center, Goodwin Research Laboratories, Virginia Commonwealth University, Richmond, VA 23298, USA.
Int J Mol Sci. 2020 Nov 26;21(23):8991. doi: 10.3390/ijms21238991.
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.
化疗和放疗通常会引起多种细胞反应，如细胞凋亡、自噬和衰老。这些过程的主要调节因子之一是 p53，它是一种重要的肿瘤抑制因子，在许多癌症类型中经常发生突变或缺失，并与早期肿瘤发生有关。功能获得（GOF）p53 突变通过损害 p53 的野生型抗肿瘤功能或调节赋予化疗耐药性的关键 p53 过程，如自噬，增加了对耐药性的易感性。自噬是一种细胞存活机制，最初是对化疗和放疗的反应而诱导的，其细胞保护特性成为了许多旨在使患者对化疗敏感的临床试验的先锋。然而，越来越多的临床前研究例证了自噬的多功能作用。此外，p53 的隔室定位可以调节自噬的诱导或抑制，并可能在自噬功能中发挥作用。p53 功能的双重性及其对自噬功能的影响在临床试验设计或临床治疗中通常不被考虑；然而，大量的临床前研究表明，它们在肿瘤对治疗和耐药性的反应中起作用。进一步研究自噬和 p53 之间的相互联系及其对化疗反应的影响，可能为多药耐药性和化学增敏的新治疗方案提供有益的见解。
