MiR-634 activates the mitochondrial apoptosis pathway and enhances chemotherapy-induced cytotoxicity

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, anti-apoptosis, 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 (ESCC), where resistance to chemotherpy remains clinically problematic. Our findings illustrate how reversing miR-634-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy.