SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

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.