SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation
SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation
复制标题
DOI：
10.1507/endocrj.ej19-0428
复制
发表时间：
2020-01-01
影响因子：
2
通讯作者：
Kawanami, Daiji
中科院分区：
文献类型：
--
作者：
Komatsu, Shiho;Nomiyama, Takashi;Kawanami, Daiji
癌症是目前2型糖尿病患者死亡的主要原因之一。我们之前报道了胰高血糖素样肽-1受体激动剂exendin-4对前列腺癌和乳腺癌的有益作用。在本研究中，我们使用乳腺癌模型检测了钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂ipragliflozin的抗癌作用。在人乳腺癌MCF-7细胞中，采用RT-PCR和免疫组织化学检测SGLT2的表达。Ipragliflozin在1 ~ 50 μ M剂量下显著且剂量依赖性地抑制MCF-7细胞的生长。BrdU实验还显示，ipragliflozin以剂量依赖的方式减弱MCF-7细胞的增殖。因为ipragliflozin对乳腺癌细胞的作用通过敲除SGLT2而被完全取消，所以ipragliflozin可以通过抑制SGLT2来起作用。接下来，我们使用膜片钳技术测量了膜电位和全细胞电流。用ipragliflozin或无糖培养基处理MCF-7细胞时，观察到膜超极化。此外，无葡萄糖培养基和siRNA敲除SGLT2抑制了葡萄糖诱导的MCF-7细胞的全细胞电流，表明ipragliflozin抑制了钠和葡萄糖通过SGLT2的共转运。ipragliflozin显著增加了JC-1绿色荧光，提示线粒体膜电位发生了变化。这些发现表明，SGLT2抑制剂ipragliflozin通过膜超极化和线粒体膜不稳定来减弱乳腺癌细胞的增殖。
Cancer is currently one of the major causes of death in patients with type 2 diabetes mellitus. We previously reported the beneficial effects of the glucagon-like peptide-1 receptor agonist exendin-4 against prostate and breast cancer. In the present study, we examined the anti-cancer effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin using a breast cancer model. In human breast cancer MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. Ipragliflozin at 1-50 mu M significantly and dose-dependently suppressed the growth of MCF-7 cells. BrdU assay also revealed that ipragliflozin attenuated the proliferation of MCF-7 cells in a dose-dependent manner. Because the effect of ipragliflozin against breast cancer cells was completely canceled by knocking down SGLT2, ipragliflozin could act via inhibiting SGLT2. We next measured membrane potential and whole-cell current using the patch clamp technique. When we treated MCF-7 cells with ipragliflozin or glucose-free medium, membrane hyperpolarization was observed. In addition, glucose-free medium and knockdown of SGLT2 by siRNA suppressed the glucose-induced whole-cell current of MCF-7 cells, suggesting that ipragliflozin inhibits sodium and glucose cotransport through SGLT2. Furthermore, JC-1 green fluorescence was significantly increased by ipragliflozin, suggesting the change of mitochondrial membrane potential. These findings suggest that the SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation via membrane hyperpolarization and mitochondrial membrane instability.