Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family.

Abstract

Resistance to platinum-based therapies arises by multiple mechanisms, including by alterations to cell-cycle kinases that mediate G(2)-M phase arrest. In this study, we conducted parallel high-throughput screens for microRNAs (miRNA) that could restore sensitivity to cisplatin-resistant cells, and we screened for kinases targeted by miRNAs that mediated cisplatin resistance. Overexpression of the cell-cycle kinases WEE1 and CHK1 occurred commonly in cisplatin-resistant cells. miRNAs in the miR-15/16/195/424/497 family were found to sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHK1. Loss-of-function and gain-of-function studies showed that miR-15 family members controlled the expression of WEE1 and CHK1. Supporting these results, we found that in the presence of cisplatin altering expression of miR-16 or related genes altered cell cycle distribution. Our findings reveal critical regulation of miRNAs and their cell-cycle-associated kinase targets in mediating resistance to cisplatin.

DOI: 10.1158/0008-5472.CAN-12-1400

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@article{Pouliot2012CisplatinSM, title={Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family.}, author={Lynn M. Pouliot and Yu-Chi Chen and Jennifer J K Bai and Rajarshi Guha and Scott E. Martin and Michael M. Gottesman and Matthew D. Hall}, journal={Cancer research}, year={2012}, volume={72 22}, pages={5945-55} }