Sensitisation of Cancer Cells to MLN8237, an Aurora-A Inhibitor, by YAP/TAZ Inactivation.

Anticancer Research
Yusuke OkuYoshimasa Uehara

Abstract

Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro. Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines. A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.

Citations

May 9, 2019·Future Oncology·Zhenxue TangGuohui Jiang
Jul 13, 2019·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Roman-Ulrich Müller, Bernhard Schermer
Jun 14, 2020·International Journal of Molecular Sciences·Lamya H Al-WahaibiGamal A Shazly

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