治疗耐药是卵巢癌患者死亡的一个显著原因。近期，多倍体巨大癌细胞（PGCCs）在化疗后肿瘤组织中常常出现，并被认为是耐药的原因之一。作为一种三型去乙酰化酶，Sirtuin1（SIRT1）在细胞周期、细胞衰老和药物耐药中起着重要作用。越来越多的证据表明，通过核质交换改变其亚细胞定位是影响SIRT1功能的关键过程。然而，SIRT1亚细胞定位在PGCC形成和随后的衰老逃逸中的作用仍不清楚。在这项研究中，我们比较了过表达野生型SIRT1（WT SIRT1）和核定位序列（NLS）突变型SIRT1（SIRT1NLSmt）的肿瘤细胞在紫杉醇治疗后PGCC的多倍体细胞群体和衰老状态之间的差异。我们研究了细胞质SIRT1在细胞周期和细胞衰老等生物过程和信号通路中对卵巢癌细胞对紫杉醇治疗的反应的影响。我们发现，SIRT1NLSmt肿瘤细胞群体中多倍体细胞较多，衰老的PGCC较少，与SIRT1过表达的肿瘤细胞群体相比。使用联合免疫沉淀（Co-IP）和液相色谱质谱（LC-MS）/质谱（MS）的比较蛋白质组学分析显示了与PGCC形成、细胞生长和死亡有关的差异表达蛋白质，如CDK1和CDK2在SIRT1NLSmt与SIRT1细胞或PGCC之间。我们的结果表明，在暴露于紫杉醇治疗中时，卵巢癌细胞利用多倍体形成作为一种存活机制，通过细胞质SIRT1对PGCC形成和存活的影响，从而增加紫杉醇的耐药性。©2023英国和爱尔兰病理学会。

Therapeutic resistance is a notable cause of death in patients with ovarian carcinoma. Polyploid giant cancer cells (PGCCs), commonly arising in tumor tissues following chemotherapy, have recently been considered to contribute to drug resistance. As a type III deacetylase, Sirtuin1 (SIRT1) plays essential roles in the cell cycle, cellular senescence, and drug resistance. Accumulating evidence has suggested that alteration in its subcellular localization via nucleocytoplasmic shuttling is a critical process influencing the functions of SIRT1. However, the roles of SIRT1 subcellular localization in PGCC formation and subsequent senescence escape remain unclear. In this study, we compared the differences in the polyploid cell population and senescence state of PGCCs following paclitaxel treatment between tumor cells overexpressing wild-type SIRT1 (WT SIRT1) and those expressing nuclear localization sequence (NLS)-mutated SIRT1 (SIRT1NLSmt ). We investigated the involvement of cytoplasmic SIRT1 in biological processes and signaling pathways, including the cell cycle and cellular senescence, in ovarian carcinoma cells' response to paclitaxel treatment. We found that the SIRT1NLSmt tumor cell population contained more polyploid cells and fewer senescent PGCCs than the SIRT1-overexpressing tumor cell population. Comparative proteomic analyses using co-immunoprecipitation (Co-IP) combined with liquid chromatography-mass spectrometry (LC-MS)/MS showed the differences in the differentially expressed proteins related to PGCC formation, cell growth, and death, including CDK1 and CDK2, between SIRT1NLSmt and SIRT1 cells or PGCCs. Our results suggested that ovarian carcinoma cells utilize polyploidy formation as a survival mechanism during exposure to paclitaxel-based treatment via the effect of cytoplasmic SIRT1 on PGCC formation and survival, thereby boosting paclitaxel resistance. © 2023 The Pathological Society of Great Britain and Ireland.© 2023 The Pathological Society of Great Britain and Ireland.