Mitotic Exit Dysfunction through the Deregulation of APC/C Characterizes Cisplatin-Resistant State in Epithelial Ovarian Cancer

Abstract

Acquired resistance to cisplatin is a major barrier to success in treatment of various cancers, and understanding mitotic mechanisms unique to cisplatin-resistant cancer cells can provide the basis for developing novel mitotic targeted therapies aimed at eradicating these cells. Using cisplatin-resistant models derived from primary patient epithelial ovarian cancer (EOC) cells, we have explored the status of mitotic exit mechanisms in cisplatin-resistant cells. We have uncovered an unexpected role of long-term cisplatin treatment in inducing mitotic exit vulnerability characterized by increased spindle checkpoint activity and functional dependency on Polo-like kinase 1 (PLK1) for mitotic exit in the presence of anaphase promoting complex/cyclosome (APC/C) dysfunction in a cisplatin-resistant state. Accordingly, PLK1 inhibition decreased the survival of cisplatin-resistant cells and and exacerbated spindle checkpoint response in these cells. APC/C inhibition increased sensitivity to pharmacologic PLK1 inhibition, further confirming the existence of APC/C dysfunction in cisplatin-resistant cells. In addition, we uncovered that resistance to volasertib, PLK1 inhibitor, is due to maintenance of cells with low PLK1 expression. Accordingly, stable PLK1 downregulation in cisplatin-resistant cells induced tolerance to volasertib. We provide the first evidence of APC/C dysfunction in cisplatin-resistant state, suggesting that understanding APC/C functions in cisplatin-resistant state could provide a basis for developing novel mitotic exit-based therapies to eradicate cisplatin-resistant cancer cells. Our results also show that PLK1 downregulation could underlie emergence of resistance to PLK1-targeted therapies in cancers. .

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

“…3 D). These results are consistent with a previous observation showing mitotic exit vulnerability driven by Anaphase Promoting Complex/Cyclosome (APC/C) dysfunction in several cisplatin-resistant models of epithelial ovarian cancer 27 .…”

“…3D). These results are consistent with a previous observation showing mitotic exit vulnerability driven www.nature.com/scientificreports/ by Anaphase Promoting Complex/Cyclosome (APC/C) dysfunction in several cisplatin-resistant models of epithelial ovarian cancer 27 . On the other hand, String pathway analysis of carboplatin-survival genes for 468-R cells showed enrichment of the G2/M checkpoint components, G2 Checkpoint Kinase WEE1, Cell Division Cycle 7 (CDC7), and CHEK1 (Fig.…”

LncRNA ANRIL Regulates Ovarian Cancer Progression and Tumor Stem Cell-Like Characteristics via miR-324-5p/Ran Axis

“… 16 Resistance to conventional cisplatin therapy is attributed to populations of cancer stem cells that possess stem-like characteristics and high tumorigenicity. 17 It was well documented that the biology of ovarian cancer stem cells and identified various markers and signaling pathways for their self-renewal ability in recent years. Targeting cancer stem cells is the most prospective strategy to overcome ovarian cancer resistance and reduce mortality.…”

The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance

“…Raab et al [82] reported that by eliminating the anti-apoptotic shielding through MCL-1 inhibition and blocking the activity of APC/C, the apoptosis-resistant and slippage prone HGSOCs were sensitized to the frontline therapy including paclitaxel. Belur Nagaraj et al [83] uncovered that longterm cisplatin treatment induced mitotic exit vulnerability in the presence of APC/C dysfunction along with cisplatin-resistance, where APC/C CDC20 inhibition increased the sensitivity of pharmacologic PLK1 inhibition, which in turn diminished cisplatin-resistant cell survival and aggravated spindle checkpoint response in cisplatin resistant ovarian cancer cells.…”