Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate

被引:69
作者
Babu, E. [1 ]
Ramachandran, S. [1 ]
CoothanKandaswamy, V. [1 ]
Elangovan, S. [1 ]
Prasad, P. D. [1 ]
Ganapathy, V. [1 ]
Thangaraju, M. [1 ]
机构
[1] Georgia Hlth Sci Univ, Med Coll Georgia, Dept Biochem & Mol Biol, Augusta, GA 30912 USA
基金
美国国家卫生研究院;
关键词
SLC5A8; dichloroacetate; anticancer drug; Warburg effect; pyruvate dehydrogenase kinase; mitochondrial oxidation in cancer; NA+-COUPLED TRANSPORTER; CANCER-CELLS; COLON-CANCER; GENE SLC5A8; ELECTROGENIC TRANSPORT; PYRUVATE-DEHYDROGENASE; PERIPHERAL NEUROPATHY; IN-VITRO; APOPTOSIS; WARBURG;
D O I
10.1038/onc.2011.113
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
There has been growing interest among the public and scientists in dichloroacetate (DCA) as a potential anticancer drug. Credible evidence exists for the antitumor activity of this compound, but high concentrations are needed for significant therapeutic effect. Unfortunately, these high concentrations produce detrimental side effects involving the nervous system, thereby precluding its use for cancer treatment. The mechanistic basis of the compound's antitumor activity is its ability to activate the pyruvate dehydrogenase complex through inhibition of pyruvate dehydrogenase kinase. As the compound inhibits the kinase at micromolar concentrations, it is not known why therapeutically prohibitive high doses are needed for suppression of tumor growth. We hypothesized that lack of effective mechanisms for the entry of DCA into tumor cells may underlie this phenomenon. Here we show that SLC5A8 transports DCA very effectively with high affinity. This transporter is expressed in normal cells, but expression is silenced in tumor cells by epigenetic mechanisms. The lack of the transporter makes tumor cells resistant to the antitumor activity of DCA. However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells and prostate cancer cells. Normal cells, which constitutively express the transporter, are however not affected by the compound, indicating tumor cell-selective therapeutic activity. The mechanism of the compound's antitumor activity still remains its ability to inhibit pyruvate dehydrogenase kinase and force mitochondrial oxidation of pyruvate. As silencing of SLC5A8 in tumors involves DNA methylation and its expression can be induced by treatment with DNA methylation inhibitors, our findings suggest that combining DCA with a DNA methylation inhibitor would offer a means to reduce the doses of DCA to avoid detrimental effects associated with high doses but without compromising antitumor activity. Oncogene (2011) 30, 4026-4037; doi:10.1038/onc. 2011.113; published online 18 April 2011
引用
收藏
页码:4026 / 4037
页数:12
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