2. Academic Validation
  3. 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

  • Cancer Lett. 2016 Mar 28;372(2):226-38. doi: 10.1016/j.canlet.2016.01.006.
Zhao Jing 1,  Xinbing Sui 1,  Junlin Yao 1,  Jiansheng Xie 2,  Liming Jiang 1,  Yubin Zhou 3,  Hongming Pan 4,  Weidong Han 5
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
  • 4 Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: hongmingpan@gmail.com.
  • 5 Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: hanwd@zju.edu.cn.
PMID: 26803057 DOI: 10.1016/j.canlet.2016.01.006
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.

Keywords

Apoptosis; Autophagy; CaMKII; Colorectal cancer; SKF-96365.

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