SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKII/AKT-mediated pathway.
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Store-operated Ca(2+) 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 II (CaMKII)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKII or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKII/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/CaMKII/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.
author list (cited authors)
Jing, Z., Sui, X., Yao, J., Xie, J., Jiang, L., Zhou, Y., Pan, H., & Han, W.
complete list of authors
Jing, Zhao||Sui, Xinbing||Yao, Junlin||Xie, Jiansheng||Jiang, Liming||Zhou, Yubin||Pan, Hongming||Han, Weidong