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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

Zhao Jing, Xinbing Sui, Junlin Yao, Jiansheng Xie, Liming Jiang, Yubin Zhou, Hongming Pan, Weidong Han

Cancer Lett. 2016 Mar 28;372(2):226-38.

PMID: 26803057

Abstract:

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 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP130495351	SKF-96365		130495-35-1	Price

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