靶向突变p53聚集体的肿瘤治疗研究进展  

Research Progress in Tumor Treatment Targeting Mutated p53 Aggregates

作　　者：王嘉健 欧霞 耿学业 张继虹 WANG Jia-Jian;OU Xia;GENG Xue-Ye;ZHANG Ji-Hong(Medical School,Kunming University of Science and Technology,Kunming 650500,China)

机构地区：[1]昆明理工大学医学院,昆明650500

出　　处：《生物化学与生物物理进展》2021年第10期1121-1129,共9页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(81960670);云南省重点项目(202001AS070012)资助。

摘　　要：突变p53(mutant p53,Mut-53)聚集体的形成是p53突变后使原本包裹在其疏水核心内部的黏附序列暴露,黏附序列迅速成核组装,形成无定形的原纤维.Mut-p53聚集体不仅可以以显性负效应(dominant-negative effect,DN)的方式使野生型p53(wild type p53,Wt-p53)失活,还表现出功能获得(gain-of-function,GOF)特性,促进肿瘤的发生和发展.在卵巢癌、结肠癌、前列腺癌等多种肿瘤细胞中均发现了Mut-p53的异常聚集,其与肿瘤的转移、耐药和预后不良具有显著的相关性.因此,p53聚集是逆转化疗耐药及肿瘤治疗的潜在靶点.设计和发现靶向Mut-p53聚集体的小分子化合物,抑制p53疏水核心内部黏附序列的暴露,恢复p53的功能从而发挥抗肿瘤作用成为了当今研究热点.本文就p53聚集体对肿瘤发生发展的影响及目前靶向Mut-p53聚集体的研究策略进行了综述.The formation of mutant p53 aggregates is caused by the exposure of the adhesion sequences wrapped in the hydrophobic core of p53 after mutation.After exposure,the adhesion sequences will quickly nucleate and assemble to form amorphous fibrils.The mutant p53 aggregates can not only inactivate wild type p53(Wt-p53)in a dominant-negative effect manner,but also exhibit gain-of-function(GOF)characteristic to promote the development and progression of tumors.Abnormal aggregation of mutant p53 has been found in various tumors,such as ovarian cancer,colon cancer and prostate cancer.The mutant p53 aggregates are significantly correlated with tumor metastasis,drug resistance and poor prognosis.Therefore,p53 aggregation is considered as a potential therapeutic target.The discovery of small molecule compounds targeting mutated p53 aggregates,which can inhibit the exposure of adhesion sequences in the hydrophobic core of p53 and restores the function of p53,is becoming a promising strategy in cancer therapy.In this review,we summarized the mechanism of p53 aggregation and the potential therapeutic strategies.

关 键 词：突变P53 聚集体 靶向策略 

分 类 号：R73[医药卫生—肿瘤] Q71[医药卫生—临床医学]