<i>mda-7/IL-24</i> Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis.

Abstract

Melanoma differentiation-associated gene-7/IL-24 (<i>mda-7/IL-24</i>) displays broad-spectrum anticancer activity <i>in vitro, in vivo</i> in preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate that <i>mda-7/IL-24</i> regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression of <i>mda-7/IL-24</i> or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death. <i>Mda-7/IL-24</i>-induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, and <i>mda-7/IL-24</i> regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221-overexpressing MDA-MB-231 clones were more aggressive and resistant to <i>mda-7/IL-24</i>-mediated cell death than parental clones. This is the first demonstration that <i>mda-7/IL-24</i> directly regulates miRNA expression in cancer cells and highlights the novelty of the <i>mda-7/IL-24</i>-miR-221-beclin-1 loop in mediating cancer cell-specific death. <i>Cancer Res; 77(4); 949-59. ©2016 AACR</i>.