Requirement of JNK signaling for self-renewal and tumor-initiating capacity of ovarian cancer stem cells

Manabu Seino; Masashi Okada; Keita Shibuya; Shizuka Seino; Shuhei Suzuki; Tsuyoshi Ohta; Hirohisa Kurachi; Chifumi Kitanaka

Requirement of JNK signaling for self-renewal and tumor-initiating capacity of ovarian cancer stem cells

Anticancer Res. 2014 Sep;34(9):4723-31.

Authors

Manabu Seino¹, Masashi Okada², Keita Shibuya³, Shizuka Seino⁴, Shuhei Suzuki⁵, Tsuyoshi Ohta⁶, Hirohisa Kurachi⁷, Chifumi Kitanaka⁸

Affiliations

¹ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan.
² Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
³ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo, Japan.
⁴ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo, Japan Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata, Japan.
⁵ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan Department of Regional Cancer Network, Yamagata University School of Medicine, Yamagata, Japan.
⁶ Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan.
⁷ Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
⁸ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo, Japan Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata, Japan ckitanak@med.id.yamagata-u.ac.jp.

PMID: 25202050

Abstract

Background/aim: Activation of the c-JUN N-terminal kinase (JNK) signaling pathway has been associated with poor survival of ovarian cancer patients, but the role(s) and significance of JNK signaling in ovarian cancer cells remain poorly understood. In the present study, we aimed to investigate the role of JNK specifically in ovarian cancer stem cells (CSCs).

Materials and methods: The effect of JNK inhibition on the self-renewal (CSC marker expression, sphere-forming ability) and tumor-initiating capacity was examined in CSCs derived from the A2780 human ovarian cancer cell line. JNK inhibition was achieved either pharmacologically or genetically by use of RNA interference.

Results: Both pharmacological and genetic targeting of JNK resulted in loss of self-renewal and tumor-initiating capacity of A2780 CSCs.

Conclusion: Our findings demonstrate, to our knowledge for the first time, that JNK has a pivotal role in the maintenance of ovarian CSCs.

Keywords: Ovarian cancer; cancer initiating cells; tumorigenicity; xenograft analysis.

Publication types

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

MeSH terms

Animals
Anthracenes / pharmacology
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Disease Models, Animal
Enzyme Activation / drug effects
Female
Gene Knockdown Techniques
Heterografts
Humans
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / genetics
JNK Mitogen-Activated Protein Kinases / metabolism*
Mice
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / mortality
Ovarian Neoplasms / pathology
Signal Transduction*
Spheroids, Cellular
Tumor Burden / drug effects
Tumor Burden / genetics
Tumor Cells, Cultured

Substances

Anthracenes
pyrazolanthrone
JNK Mitogen-Activated Protein Kinases