Cai Hao, Zhang Yunhui, Han Tianxiang Kevin, Everett Ruth S, Thakker Dhiren R
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
Research Center for Drug Metabolism, Jilin University, Changchun, People's Republic of China.
Int J Cancer. 2016 May 1;138(9):2281-92. doi: 10.1002/ijc.29965. Epub 2016 Jan 8.
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.
抗糖尿病药物二甲双胍对乳腺癌和其他癌症具有抗肿瘤作用。据信二甲双胍发挥其抗癌作用的一种机制涉及激活其细胞内靶点——腺苷单磷酸激活的蛋白激酶（AMPK），这也与二甲双胍的抗糖尿病作用有关。有人提出，在癌细胞中，AMPK激活会导致对雷帕霉素哺乳动物靶点（mTOR）和调节细胞增殖的下游pS6K的抑制。由于其亲水性和阳离子性质，二甲双胍需要阳离子选择性转运体进入细胞并激活AMPK。本研究表明，阳离子选择性转运体的表达水平与二甲双胍在乳腺癌中的抗增殖和抗肿瘤疗效相关。在缺乏阳离子选择性转运体的人乳腺癌细胞系BT - 20和经基因工程改造以过表达有机阳离子转运体3（OCT3）的BT - 20细胞系之间比较了二甲双胍的摄取和抗增殖活性，OCT3是阳离子选择性转运体的代表，也是人乳腺肿瘤中的主要转运体。二甲双胍在BT - 20细胞中的摄取极少，但在OCT3 - BT20细胞中增加了13倍以上，其抗增殖效力在OCT3 - BT20细胞中是BT - 20细胞的4倍以上。这种抗增殖活性的增加与OCT3 - BT20细胞中更大的AMPK磷酸化和降低的pS6K磷酸化有关。体内观察结果证实了体外数据，即在携带过表达OCT3肿瘤的异种移植小鼠中，二甲双胍的抗肿瘤疗效明显高于低转运体表达的野生型肿瘤。总的来说，这些发现确立了阳离子选择性转运体表达、AMPK - mTOR - pS6K信号级联与二甲双胍在乳腺癌中的抗增殖活性之间的明确关系。
Zotero 插件