J Cancer 2019; 10(24):6037-6047. doi:10.7150/jca.34650

Research Paper

Dichloroacetate Overcomes Oxaliplatin Chemoresistance in Colorectal Cancer through the miR-543/PTEN/Akt/mTOR Pathway

Yu Liang1*, Danxi Zhu1*, Liming Zhu1, Yichao Hou1, Lidan Hou1, Xin Huang1, Linjing Li1, Yu Wang1, Lei Li1, Huimin Zou1, Tianqi Wu2, Mengfei Yao2, Jianhua Wang2, Xiangjun Meng1✉

1. Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Cancer institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
*These authors contributed equally to this work.

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Citation:
Liang Y, Zhu D, Zhu L, Hou Y, Hou L, Huang X, Li L, Wang Y, Li L, Zou H, Wu T, Yao M, Wang J, Meng X. Dichloroacetate Overcomes Oxaliplatin Chemoresistance in Colorectal Cancer through the miR-543/PTEN/Akt/mTOR Pathway. J Cancer 2019; 10(24):6037-6047. doi:10.7150/jca.34650. Available from http://www.jcancer.org/v10p6037.htm

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Abstract

Chemoresistance is responsible for most colorectal cancer (CRC) related deaths. In this study, we found that dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, can be used as a sensitizer for oxaliplatin (L-OHP) chemoresistant CRC cells. The aim of this study was to explore the ability of DCA to overcome L-OHP resistance in CRC cells and to identify the underlying molecular mechanisms. We found that DCA sensitizes chemoresistant CRC cells to L-OHP-induced cytotoxic effects by inhibiting clone formation capacity and promoting cell apoptosis. A microRNA (miRNA) array was used for screen, and miR-543 was identified and shown to be downregulated after DCA treatment. The expression of miR-543 was higher in chemoresistant CRC cells than in chemosensitive CRC cells. Overexpression of miR-543 increased chemoresistance in CRC cells. The validated target gene, PTEN, was negatively regulated by miR-543 both in vitro and in vivo, and PTEN was upregulated by DCA through miR-543. In addition, overexpression of miR-543 reversed the inhibition of colony formation after DCA treatment. Furthermore, the Akt/mTOR pathway is activated by miR-543 and is involved in the miR-543 induced chemoresistance. There was a significant inverse relationship between miR-543 expression and PTEN level in CRC patients, and high miR-543 expression was associated with worse prognosis. In conclusion, DCA restored chemosensitivity through miR-543/PTEN/Akt/mTOR pathway, and miR-543 may be a potential marker or therapeutic target for chemoresistance in CRC.

Keywords: colorectal cancer, oxaliplatin, chemoresistance, miR-543 colorectal cancer, oxaliplatin, chemoresistance, miR-543