Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan.
Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan.
Exp Cell Res. 2013 Aug 1;319(13):1913-1921. doi: 10.1016/j.yexcr.2013.05.031. Epub 2013 Jun 11.
In addition to potent anticancer effects of selenite, a modest therapeutic effect of sodium selenate has been demonstrated in prostate cancer patients. Selenate acts by activating protein phosphatase 2A, which inhibits various signal transduction cascades, including the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The human colorectal carcinoma cell line DLD-1 harbors a constitutive active mutation in PIK3CA encoding the PI3K p110α catalytic subunit. Thus, we examined the anticancer effect of sodium selenate in DLD-1 cells. As expected, selenate significantly decreased cell viability and increased apoptosis at a 50% inhibitory concentration (IC50) of 0.88mM, whereas selenite was much more potent at an IC50 of 0.0061mM. Surprisingly, at lower concentrations (0.04-0.16mM), selenate induced changes in cell morphology and motility that are characteristic of the epithelial-mesenchymal transition (EMT). Moreover, selenate-induced EMT was associated with AKT activation, increased expression of the EMT-inducing transcription factor TWIST1 and the mesenchymal cell-specific intermediate filament vimentin, and decreased expression of the epithelial cell-specific adhesion molecule E-cadherin. The critical role of AKT activation in selenate-induced EMT was identified using the AKT inhibitor Akti-1/2, which suppressed EMT-associated cell motility and invasion. These results suggest that although sodium selenate is a potential anticancer drug, deleterious effects of EMT induction should be taken into careful consideration.
除了亚硒酸盐具有强大的抗癌作用外，亚硒酸钠在前列腺癌患者中也表现出适度的治疗效果。亚硒酸盐通过激活蛋白磷酸酶 2A 起作用，后者抑制包括磷脂酰肌醇 3-激酶（PI3K）/ AKT 途径在内的各种信号转导级联。人结直肠癌细胞系 DLD-1 携带编码 PI3K p110α 催化亚基的 PIK3CA 的组成性激活突变。因此，我们研究了亚硒酸钠对 DLD-1 细胞的抗癌作用。不出所料，亚硒酸盐在 50%抑制浓度（IC50）为 0.88mM 时显著降低细胞活力并增加细胞凋亡，而亚硒酸盐在 IC50 为 0.0061mM 时更有效。令人惊讶的是，在较低浓度（0.04-0.16mM）下，亚硒酸盐诱导细胞形态和运动的变化，这些变化是上皮-间充质转化（EMT）的特征。此外，亚硒酸盐诱导的 EMT 与 AKT 激活、上皮间充质转化诱导转录因子 TWIST1 和间充质细胞特异性中间丝波形蛋白表达增加以及上皮细胞特异性粘附分子 E-钙粘蛋白表达减少有关。使用 AKT 抑制剂 Akti-1/2 鉴定 AKT 激活在亚硒酸盐诱导的 EMT 中的关键作用，该抑制剂抑制 EMT 相关的细胞迁移和侵袭。这些结果表明，尽管亚硒酸钠是一种潜在的抗癌药物，但 EMT 诱导的有害影响应引起谨慎考虑。
