Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells

Abstract

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.

Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling

“…In addition, PRL-3 also promotes the formation of grossly hyperdiploid and multinucleated cancer cells known as polyploid giant cells (PGCCs), which typically appear in tumor tissue after chemotherapy, forming a stem cell-like pool that promotes cell survival, chemotherapy resistance, and tumor recurrence [ 141 , 142 ].…”

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

“…Consequently, the formation of PGCCs may be a significant cellular response to AURK inhibitors, potentially leading to treatment resistance or tumor recurrence. Recently, H. Xu et al found that Sirtuin1 (SIRT1), a type III deacetylase, is overexpressed in the cytoplasm and promotes drug resistance in ovarian cancer cells after paclitaxel treatment by increasing PGCC formation and allowing cells to escape senescence ( Xu et al, 2023 ). Additionally, cytoplasmic SIRT1 may play a role in polyploidization by promoting the binding of cyclin B and CDK1 ( Xu et al, 2023 ).…”

“…Recently, H. Xu et al found that Sirtuin1 (SIRT1), a type III deacetylase, is overexpressed in the cytoplasm and promotes drug resistance in ovarian cancer cells after paclitaxel treatment by increasing PGCC formation and allowing cells to escape senescence ( Xu et al, 2023 ). Additionally, cytoplasmic SIRT1 may play a role in polyploidization by promoting the binding of cyclin B and CDK1 ( Xu et al, 2023 ). Ovarian cancer cells gain a survival advantage through polyploidization, which is a key mechanism for generating chemotherapy resistance.…”