miR-634 Activates the Mitochondrial Apoptosis Pathway and Enhances Chemotherapy-Induced Cytotoxicity.

Abstract

Some tumor-suppressing miRNAs target multiple oncogenes concurrently and therefore may be useful as cancer therapeutic agents. Further, such miRNAs may be useful to address chemotherapeutic resistance in cancer, which remains a primary clinical challenge in need of solutions. Thus, cytoprotective processes upregulated in cancer cells that are resistant to chemotherapy are a logical target for investigation. Here, we report that overexpression of miR-634 activates the mitochondrial apoptotic pathway by direct concurrent targeting of genes associated with mitochondrial homeostasis, antiapoptosis, antioxidant ability, and autophagy. In particular, we show how enforced expression of miR-634 enhanced chemotherapy-induced cytotoxicity in a model of esophageal squamous cell carcinoma, where resistance to chemotherapy remains clinically problematic. Our findings illustrate how reversing miR-634-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy.