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

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.

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

“…For instance, the deletion of CDKN2A, which encodes the tumor suppressors p14 and p16 by alternative splicing, may affect the p14-mediated accumulation of p53 and ensuing activation (Midgley et al 2000). Noteworthy, deletion of 9p21.3 harbors the mirR-491, which was recently reported to have pro-apoptotic activity by targeting both BCL-XL and MCL1 proteins in chemoresistant ovarian cancer cell lines (Denoyelle et al 2014), as well as miR-31, whose genomic deletion has been correlated with defects in the p53 pathway in cancer cells (Creighton et al 2010). Decreased miR-31 expression was also reported to enhance chemoresistance of ovarian cancer cells due to up-regulation of its target, receptor tyrosine kinase MET (Mitamura et al 2013).…”

The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737

“…In ovarian cancers, we previously showed that Bcl-x L and Mcl-1 antiapoptotic proteins cooperate to protect resistant cells from apoptosis as their concomitant inhibition results in massive apoptotic cell death (5-7). Moreover, there is growing evidence to suggest that their BH3-only proapoptotic partner Bim is a crucial actor in induced cell death (8)(9)(10). These observations open up several therapeutic opportunities as they suggest that ovarian cancer cell apoptosis can be triggered by inhibiting Bcl-x L and Mcl-1 and/or by promoting their BH3-only partners, especially Bim.…”

Epigallocatechin-3-gallate inhibits paclitaxel-induced apoptosis through the alteration of microRNA expression in human dermal papilla cells

“…When FOXO1 is overexpressed, cell proliferation and growth is inhibited by upregulating caspase-3 and caspase-9 and inducing G2/M arrest and (Yang et al 2015). BCL2L1 and BCL2L2, BCL2 family, are pro-oncogene and repress intrinsic pathwaymediated cell death (Denoyelle et al 2014;Zhang et al 2015). Other genes, PTEN, BBC3, and MDM2, also rescue cell death and induce proliferation (Fortunato et al 2014;Zhang et al 2010).…”