Int J Med Sci 2019; 16(5):636-643. doi:10.7150/ijms.30889

Research Paper

Eicosapentaenoic acids enhance chemosensitivity through connexin 43 upregulation in murine melanoma models

Chih-Jen Yang1,2,3, Chi-Te Kuo4, Li-Hsien Wu5, Man-Chin Chen5, Christian Ronquillo Pangilinan5, Naphichaya Phacharapiyangkul6, Wangta Liu7, Ya-Huey Chen8,9, Che-Hsin Lee5,10✉

1. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;
2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;
3. Faculty of Medicine, Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Taiwan;
4. Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan;
5. Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan;
6. Faculty of Pharmacy, Mahidol University, Bangkok, Thailand;
7. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan;
8. Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
9. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
10. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

Abstract

Chemotherapy is now in common use for the treatment of tumors; however, with tumor growth retardation comes the severe side effects that occur after a chemotherapy cycle. Eicosapentaenoic acids (EPA) used in combination with chemotherapy has an additive effects and provides a rationale for using EPA in tandem with chemotherapy. To improve the efficacy and safety of this combination therapy, a further understanding that EPA modulates with the tumor microenvironment is necessary. Connexin 43 (Cx43) is involved in enhancing chemosensitivity that was suppressed in a tumor microenvironment. We aim to investigate the role of EPA in chemosensitivity in murine melanoma by inducing Cx43 expression. The dose-dependent upregulation of Cx43 expression and gap junction intercellular communication were observed in B16F10 cells after EPA treatment. Furthermore, EPA significantly increased the expression levels of mitogen-activated protein kinases (MAPK) signaling pathways. The EPA-induced Cx43 expression was reduced after MAPK inhibitors. Knockdown Cx43 in B16F10 cells reduced the therapeutic effects of combination therapy (EPA plus 5-Fluorouracil). Our results demonstrate that the treatment of EPA is a tumor induced Cx43 gap junction communication and enhances the combination of EPA and chemotherapeutic effects.

Keywords: Eicosapentaenoic acids, Connexin 43, 5-Fluorouracil, combination therapy

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How to cite this article:
Yang CJ, Kuo CT, Wu LH, Chen MC, Pangilinan CR, Phacharapiyangkul N, Liu W, Chen YH, Lee CH. Eicosapentaenoic acids enhance chemosensitivity through connexin 43 upregulation in murine melanoma models. Int J Med Sci 2019; 16(5):636-643. doi:10.7150/ijms.30889. Available from http://www.medsci.org/v16p0636.htm