Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

Karolina Weiner-Gorzel, Eugene Dempsey, Malgorzata Milewska, Aloysius McGoldrick, Valerie Toh, Aoibheann Walsh, Sinead Lindsay, Luke Gubbins, Aoife Cannon, Daniel Sharpe, Jacintha O'Sullivan, Madeline Murphy, Stephen F. Madden, Malcolm Kell, Amanda McCann, Fiona Furlong

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Abstract

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in β-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence.
Original languageEnglish
Pages (from-to)745-758
Number of pages14
JournalCancer Medicine
Volume4
Issue number5
Early online date15 Feb 2015
DOIs
Publication statusPublished - May 2015

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    Weiner-Gorzel, K., Dempsey, E., Milewska, M., McGoldrick, A., Toh, V., Walsh, A., Lindsay, S., Gubbins, L., Cannon, A., Sharpe, D., O'Sullivan, J., Murphy, M., Madden, S. F., Kell, M., McCann, A., & Furlong, F. (2015). Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells. Cancer Medicine, 4(5), 745-758. https://doi.org/10.1002/cam4.409