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

Naoto Fujiwara; Jun Inoue; Tatsuyuki Kawano; Kousuke Tanimoto; Ken-Ichi Kozaki; Johji Inazawa

doi:10.1158/0008-5472.CAN-15-0257

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

Cancer Res. 2015 Sep 15;75(18):3890-901. doi: 10.1158/0008-5472.CAN-15-0257. Epub 2015 Jul 27.

Authors

Naoto Fujiwara¹, Jun Inoue², Tatsuyuki Kawano³, Kousuke Tanimoto², Ken-Ichi Kozaki⁴, Johji Inazawa⁵

Affiliations

¹ Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan. Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
² Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan.
³ Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Department of Dental Pharmacology, Graduate School, Okayama University, Okayama, Japan.
⁵ Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan. Department of Genome Medicine, Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan. Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan. johinaz.cgen@mri.tmd.ac.jp.

PMID: 26216549
DOI: 10.1158/0008-5472.CAN-15-0257

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
RNA, Neoplasm / genetics*
RNA, Neoplasm / therapeutic use
RNA, Small Interfering / genetics
RNA, Small Interfering / pharmacology
Reactive Oxygen Species
Transfection
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Alkylating
MIRN-634 microRNA, human
MicroRNAs
Neoplasm Proteins
RNA, Neoplasm
RNA, Small Interfering
Reactive Oxygen Species
Cisplatin