title: Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion.
abstract: Global downregulation of microRNAs (miRNAs) is a common feature of human tumors and has been shown to enhance cancer progression. Several components of the miRNA biogenesis machinery (XPO5, DICER and TRBP) have been shown to act as haploinsufficient tumor suppressors. How the deregulation of miRNA biogenesis promotes tumor development is not clearly understood. Here we show that loss of miRNA biogenesis increased resistance to endoplasmic reticulum (ER) stress-induced cell death. We observed that HCT116 cells with a DICER hypomorphic mutation (Exn5/Exn5) or where DICER or DROSHA were knocked down were resistant to ER stress-induced cell death. Extensive analysis revealed little difference in the unfolded protein response (UPR) of WT compared to Exn5/Exn5 HCT116 cells upon ER stress treatment. However, analysis of the intrinsic apoptotic pathway showed that resistance occurred upstream of the mitochondria. In particular, BAX activation and dissipation of mitochondrial membrane potential was attenuated, and there was altered expression of BCL-2 family proteins. These observations demonstrate a key role for miRNAs as critical modulators of the ER stress response. In our model, downregulation of miRNA biogenesis delays ER stress-induced apoptosis. This suggests that disrupted miRNA biogenesis may contribute to cancer progression by inhibiting ER stress-induced cell death.
authors: Apoptosis Research Centre, National University of Ireland, Galway, Ireland.
authors: Karen
authors: K
authors: Cawley
authors: Susan E
authors: SE
authors: Logue
authors: Adrienne M
authors: AM
authors: Gorman
authors: Qingping
authors: Q
authors: Zeng
authors: John
authors: J
authors: Patterson
authors: Sanjeev
authors: S
authors: Gupta
authors: Afshin
authors: A
authors: Samali
mesh_terms: D016923:Cell Death; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D008928:Mitochondria / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C517918:DROSHA protein, human; D043244:Ribonuclease III
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