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Cation‐selective transporters are critical to the AMPK‐mediated antiproliferative effects of metformin in human breast cancer cells
Author(s) -
Cai Hao,
Zhang Yunhui,
Han Tianxiang Kevin,
Everett Ruth S.,
Thakker Dhiren R.
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29965
Subject(s) - metformin , ampk , organic cation transport proteins , cancer research , cancer cell , chemistry , pharmacology , pi3k/akt/mtor pathway , glucose transporter , transporter , cancer , microbiology and biotechnology , endocrinology , medicine , kinase , protein kinase a , biology , biochemistry , signal transduction , diabetes mellitus , gene , insulin
The antidiabetic drug metformin exerts antineoplastic effects against breast cancer and other cancers. One mechanism by which metformin is believed to exert its anticancer effect involves activation of its intracellular target, adenosine monophosphate‐activated protein kinase (AMPK), which is also implicated in the antidiabetic effect of metformin. It is proposed that in cancer cells, AMPK activation leads to inhibition of the mammalian target of rapamycin (mTOR) and the downstream pS6K that regulates cell proliferation. Due to its hydrophilic and cationic nature, metformin requires cation‐selective transporters to enter cells and activate AMPK. This study demonstrates that expression levels of cation‐selective transporters correlate with the antiproliferative and antitumor efficacy of metformin in breast cancer. Metformin uptake and antiproliferative activity were compared between a cation‐selective transporter‐deficient human breast cancer cell line, BT‐20, and a BT‐20 cell line that was engineered to overexpress organic cation transporter 3 (OCT3), a representative of cation‐selective transporters and a predominant transporter in human breast tumors. Metformin uptake was minimal in BT‐20 cells, but increased by >13‐fold in OCT3‐BT20 cells, and its antiproliferative potency was >4‐fold in OCT3‐BT20 versus BT‐20 cells. This increase in antiproliferative activity was associated with greater AMPK phosphorylation and decreased pS6K phosphorylation in OCT3‐BT20 cells. In vitro data were corroborated by in vivo observations of significantly greater antitumor efficacy of metformin in xenograft mice bearing OCT3‐overexpressing tumors versus low transporter‐expressing wildtype tumors. Collectively, these findings establish a clear relationship between cation‐selective transporter expression, the AMPK‐mTOR‐pS6K signaling cascade, and the antiproliferative activity of metformin in breast cancer.