Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway.
Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway.
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DOI：
10.1016/j.biopha.2020.110821
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发表时间：
2020-10
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通讯作者：
Jun Zhou;Jin Zhu;Sheng-Jian Yu;Huai-Lu Ma;Jie Chen;Xiaofei Ding;Guang Chen;Yong Liang;Qiang Zhang
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文献类型：
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作者：
Jun Zhou;Jin Zhu;Sheng-Jian Yu;Huai-Lu Ma;Jie Chen;Xiaofei Ding;Guang Chen;Yong Liang;Qiang Zhang
目的钠-葡萄糖转运体2(SGLT2)抑制剂Canagliflzin和Dapagliflzin是新近批准的治疗2型糖尿病的药物。最近的研究表明，SGLT2抑制剂有可能抑制表达SGLT2的癌细胞的生长，但对SGLT2抑制剂在乳腺癌中的作用知之甚少。本研究的目的是评价SGLT2抑制剂在体外和体内的抗癌活性。方法采用免疫组织化学和免疫印迹法检测SGLT2在乳腺癌组织中的表达。采用四甲基偶氮唑蓝细胞毒实验、集落形成实验和人乳腺癌细胞裸鼠移植模型，检测SGLT2抑制剂对癌细胞增殖和生长的影响。流式细胞仪检测SGLT2抑制剂是否诱导细胞周期停滞和细胞凋亡。四甲基偶氮唑盐比色法、体外克隆存活实验和体内异种移植生长模型显示，SGLT2抑制剂达帕格列酮和卡那格列酮对乳腺癌细胞有明显的抑制增殖作用。此外，我们还发现SGLT2抑制剂使细胞周期停滞在G1/G0期，并诱导细胞凋亡。Western印迹分析显示SGLT2抑制剂可使乳腺癌细胞AMPK的磷酸化水平升高，70 kDa核糖体蛋白S6K1(P70S6K1)的磷酸化水平降低。结论SGLT2抑制剂可诱导AMPK介导的细胞周期停滞和细胞凋亡，为乳腺癌的治疗提供了一种新的策略。
ObjectiveThe sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate the potential ability of SGLT2 inhibitors to attenuate cancer growth of SGLT2-expressing cancer cells, but there is little known about the effects of SGLT2 inhibitors on breast cancer. The goal in this research was to assess the anticancer activity of SGLT2 inhibitors in breast cancerin vitroandin vivo.MethodsWe test the SGLT2 expression in breast cancer using immunohistochemistry and immunoblot assay. MTT cytotoxicity assay, colony formation assay and human breast cancer cells nude mice xenograft model were performed to detect the effects of SGLT2 inhibitors on cancer cell proliferation and growth. Flow Cytometry assay was performed to determine if the SGLT2 inhibitors induced cell cycle arrest and apoptosis.ResultsWe proved that SGLT2 expresses in breast cancer cell lines and human breast tumor tissue samples. SGLT2 inhibitors Dapagliflozin and Canagliflozin exhibited a potent anti-proliferative effect in breast cancer cells as demonstrated by MTT, clonogenic survival assayin vitroand xenograft growth modelin vivo. Furthermore, we found that SGLT2 inhibitors arrested cell cycle in G1/G0 phase and induced cell apoptosis. Western blot analysis demonstrated that treatment with SGLT2 inhibitors increased the phosphorylation of Amp-activated protein kinase (AMPK) and decreased the phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (p70S6K1) in breast cancer cells.ConclusionsThese findings indicate that SGLT2 inhibitor-therapy induced AMPK-mediated cell cycle arrest and apoptosis, which is a potential novel strategy for the treatment of breast cancer.