SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway.
SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway.
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SKF-96365 通过抑制钙/CaMKII gamma/AKT 介导的途径激活细胞保护性自噬以延迟结直肠癌细胞的凋亡
DOI：
10.1016/j.canlet.2016.01.006
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发表时间：
2016-03-28
期刊：
影响因子：
9.7
通讯作者：
Han W
中科院分区：
文献类型：
--
作者：
Jing Z;Sui X;Yao J;Xie J;Jiang L;Zhou Y;Pan H;Han W
钙库操纵的钙离子内流抑制剂（SOCE）正成为新一代有吸引力的抗癌药物。在这里，我们报告SKF-96365，SOCE抑制剂，通过诱导结直肠癌细胞的细胞周期阻滞和凋亡，表现出有效的抗肿瘤活性。同时，SKF-96365还通过阻止细胞色素c（cyt c）从线粒体释放到细胞质中，诱导细胞保护性自噬以延迟细胞凋亡。从机制上讲，SKF-96365处理在体外和体内抑制钙/钙调蛋白依赖性蛋白激酶IIγ（CaMKIIγ）/AKT信号级联反应。CaMKIIγ或AKT的过表达消除了SKF-96365对癌细胞的作用，表明CaMKIIγ/AKT信号通路在SFK-96365诱导的生物学效应中起着关键作用。此外，FDA批准的用于抑制自噬的药物羟氯喹（HCQ）可以显著增强SFK-96365在小鼠异种移植模型中的抗癌作用。据我们所知，这是第一份证明钙/CaMKIIγ/AKT信号转导可以同时调节癌细胞凋亡和自噬的报告，SOCE抑制剂SKF-96365与自噬抑制剂的组合代表了治疗结直肠癌患者的有希望的策略。
Store-operated Ca2+ entry (SOCE) inhibitors are emerging as an attractive new generation of anti-cancer drugs. Here, we report that SKF-96365, an SOCE inhibitor, exhibits potent anti-neoplastic activity by inducing cell-cycle arrest and apoptosis in colorectal cancer cells. In the meantime, SKF-96365 also induces cytoprotective autophagy to delay apoptosis by preventing the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm. Mechanistically, SKF-96365 treatment inhibited the calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKIIγ or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKIIγ/AKT signaling pathway in SFK-96365-induced biological effects. Moreover, Hydroxychloroquine (HCQ), an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-cancer effect of SFK-96365 in a mouse xenograft model. To our best knowledge, this is the first report to demonstrate that calcium/CaMKIIγ/AKT signaling can regulate apoptosis and autophagy simultaneously in cancer cells, and the combination of the SOCE inhibitor SKF-96365 with autophagy inhibitors represents a promising strategy for treating patients with colorectal cancer.