MiR-491-5p-induced apoptosis in ovarian carcinoma depends on the direct inhibition of both BCL-XL and EGFR leading to BIM activation.

C Denoyelle,E Brotin,N Vigneron,M-H Louis,B Lambert,P Gauduchon,F Giffard,C Lecerf,P Juin,E Abeilard,L Poulain,M Meryet-Figuière

doi:10.1038/cddis.2014.389

Abstract

We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-XL and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-XL expression and by inducing BIM accumulation in its dephosphorylated form. This latter effect is due to direct targeting of epidermal growth factor receptor (EGFR) by miR-491-5p and consequent inhibition of downstream AKT and MAPK signalling pathways. Induction of apoptosis by miR-491-5p in this cell line is mimicked by a combination of EGFR inhibition together with a BH3-mimetic molecule. In contrast, SKOV3 cells treated with miR-491-5p maintain AKT and MAPK activity, do not induce BIM and do not undergo cell death despite BCL-XL and EGFR downregulation. In this cell line, sensitivity to miR-491-5p is restored by inhibition of both AKT and MAPK signalling pathways. Altogether, this work highlights the potential of miRNA functional studies to decipher cell signalling pathways or major regulatory hubs involved in cell survival to finally propose the rationale design of new strategies on the basis of pharmacological combinations.

Highlights

Escape from apoptosis is an almost systematic hallmark of cancer cells that contributes to tumor progression and drug resistance.[3]
To identify potential miRNAs that could induce apoptosis in ovarian cancer cell lines, we performed an in silico search for putative miRNAs that could target BCL-XL using miRNA targetprediction tools[16] (Supplementary Figure S1)
Each of the 11 selected miRNAs was transfected into two chemoresistant ovarian carcinoma cell lines (IGROV1-R10 and SKOV3) and cell proliferation was analysed (Supplementary Figure S2)

Summary

Introduction

Escape from apoptosis is an almost systematic hallmark of cancer cells that contributes to tumor progression and drug resistance.[3]. The level of BIM was strongly increased in response to miR-4915p in IGROV1-R10 cells, whereas it remained unchanged after transfection with an miRNA control or siRNA targeting BCL-XL (Supplementary Figure S7).

Results

Conclusion