MRC Toxicology Unit, University of Cambridge, Cambridge, UK.
Avacta Life Sciences, Cambridge, UK.
Cell Death Dis. 2021 Feb 24;12(2):207. doi: 10.1038/s41419-021-03497-y.
TP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.
TP53 是癌症中最常发生突变的基因。突变导致 p53 表达缺失或突变蛋白的表达。突变型 p53 蛋白通常丧失野生型功能，但也可获得促进转移和化疗耐药的新功能。先前，我们发现 Rab 衔接蛋白（RCP）在突变型 p53 依赖性侵袭中起作用。RCP 促进内体循环和整合素及受体酪氨酸激酶的信号转导。在筛选鉴定新的 RCP 相互作用蛋白的过程中，我们发现了 P 糖蛋白（P-gp）。因此，我们假设突变型 p53 可以通过 RCP 依赖性 P-gp 循环来促进化疗耐药性。RCP 和 P-gp 之间的相互作用在体内得到了验证，并且缺失 RCP 或突变型 p53 使细胞对顺铂和依托泊苷更加敏感。在突变型 p53 细胞中，我们在药物处理时检测到 RCP 依赖性 P-gp 向质膜的转运，并减少了 P-gp 底物的保留。在化疗药物暴露时，突变型 p53 细胞中观察到 P-gp 和 RCP 的共定位，但在 p53 缺失细胞中没有观察到。总之，突变型 p53 的表达增强了 P-gp 和 RCP 的共定位，从而允许 P-gp 快速转运到质膜，并增加对化疗药物的耐药性。
