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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-09, Vol.75 (18), p.3890-3901
• Main Authors: Fujiwara, Naoto, Inoue, Jun, Kawano, Tatsuyuki, Tanimoto, Kousuke, Kozaki, Ken-Ichi, Inazawa, Johji
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis - genetics; Autophagy - genetics; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - therapy; Cell Line, Tumor; Cisplatin - pharmacology; Cisplatin - therapeutic use; Combined Modality Therapy; Drug Resistance, Neoplasm; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - pathology; Esophageal Neoplasms - therapy; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - genetics; Genetic Therapy; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - therapeutic use; Mitochondria - physiology; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Organelle Biogenesis; Oxidative Stress; Reactive Oxygen Species; RNA, Neoplasm - genetics; RNA, Neoplasm - therapeutic use; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Transfection; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-15-0257

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.