Resveratrol Enhances Chemosensitivity in Mouse Melanoma Model Through Connexin 43 Upregulation.
Although current studies indicate that resveratrol exhibits potential antitumor activities, the precise mechanisms of its beneficial effects combined with chemotherapy are not fully understood. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of resveratrol and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Gap junctions mediate cell communication by allowing the passage of molecules from one cell to another. Connexin (Cx) 43 is ubiquitous and reduced in a variety of tumor cells. Cx43 may influence the response of tumor cells to treatments by facilitating the passage of antitumor drugs or death signals between neighboring tumor cells. Following resveratrol treatment, dose-dependent upregulation of Cx43 expressions was observed. In addition, gap junction intercellular communication was increased. To study the mechanism underlying these resveratrol-induced Cx43 expressions, we found that resveratrol induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The MAPK inhibitors significantly reduced the expression of Cx43 protein after resveratrol treatment. Specific knockdown of Cx43 resulted in a reduction of cell death after resveratrol and cisplatin treatment. Our results suggest that treatment of resveratrol in tumor leads to increase Cx43 gap junction communication and enhances the combination of resveratrol and cisplatin therapeutic effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 877-886, 2015.
Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan.
Yu-Jung
YJ
Cheng
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.|Department of Medical Research, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan.
Meng-Ya
MY
Chang
Department of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
Wen-Wei
WW
Chang
Department of Environmental Engineering and Science, Feng Chia University, Taichung, Taiwan.
Wei-Kuang
WK
Wang
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
Chi-Fan
CF
Liu
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
Song-Tao
ST
Lin
Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Microbiology, School of Medicine, China Medical University, Taichung, Taiwan.
Che-Hsin
CH
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018031:Connexin 43; C543076:GJA1 protein, mouse; D013267:Stilbenes; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin; D000077185:Resveratrol
cisplatin; connexin 43; gap junctions; resveratrol