Bai Zhaoshi, Zhou Yiran, Ye Xinyue, Li Yupeng, Peng Yaling, Guan Qi, Zhang Weige, Ma Lingman
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China.
Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Biochim Biophys Acta Mol Cell Res. 2022 Feb;1869(2):119174. doi: 10.1016/j.bbamcr.2021.119174. Epub 2021 Nov 20.
Mitotic catastrophe (MC) is a newly identified type of anticancer mechanism for multidrug resistance (MDR) prevention. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. BZML is a novel colchicine-binding site inhibitor which can overcome MDR by inducing MC; however, BZML-induced MC cells underwent a long cellular death process. Thus, to improve anticancer therapies based on drug-induced MC, BZML-induced MC was served as a model to further study the underlying molecular mechanisms in the process of MC. Here, BZML could induce p53-dependent senescence in A549/Taxol cells, a MDR cell line. This senescence was a secondary effect of MC in overcoming MDR. During MC, BZML-induced destruction of protein-degradation system contributed not only to an increase of p53 protein but also to the accumulation of survivin in nucleus of A549/Taxol cells. Importantly, the nuclear accumulation of survivin was not the inducer but the result of BZML-induced MC, and it promoted the survival of senescent cells. Moreover, it provided additional vulnerability and critical opportunities for sequentially applied therapies. Further, targeting survivin with YM155 accelerated the death of MC cells by timely eliminating therapy-induced senescent cells and strengthening the efficiency of BZML in overcoming MDR in A549/Taxol cells. Collectively, nuclear accumulation of survivin delayed cellular death during MC by promoting the survival of BZML-induced senescent A549/Taxol cells. Moreover, "one-two punch" approach to cancer treatment based on combination therapy with YM155 for survivin suppression might be a new strategy for potentiating MC to overcome MDR.
有丝分裂灾难（MC）是一种新发现的预防多药耐药（MDR）的抗癌机制。然而，MC导致的漫长细胞死亡过程对抗癌治疗并无益处。BZML是一种新型秋水仙碱结合位点抑制剂，它可通过诱导MC来克服MDR；然而，BZML诱导的MC细胞经历了漫长的细胞死亡过程。因此，为了改进基于药物诱导MC的抗癌疗法，以BZML诱导的MC作为模型来进一步研究MC过程中的潜在分子机制。在此，BZML可在多药耐药细胞系A549/Taxol细胞中诱导p53依赖性衰老。这种衰老是MC克服MDR的一种继发效应。在MC过程中，BZML诱导的蛋白质降解系统破坏不仅导致p53蛋白增加，还导致survivin在A549/Taxol细胞核中积累。重要的是，survivin的核积累不是BZML诱导MC的诱导因素，而是其结果，并且它促进了衰老细胞的存活。此外，它为序贯应用的疗法提供了额外的脆弱性和关键机会。进一步地，用YM155靶向survivin可通过及时清除治疗诱导的衰老细胞并增强BZML克服A549/Taxol细胞中MDR的效率来加速MC细胞的死亡。总的来说，survivin的核积累通过促进BZML诱导的衰老A549/Taxol细胞的存活来延迟MC期间的细胞死亡。此外，基于与YM155联合治疗以抑制survivin的“组合拳”癌症治疗方法可能是增强MC以克服MDR的一种新策略。
