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

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 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.

SUBMITTER: Jing Z

PROVIDER: S-EPMC5240807 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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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.

Jing Zhao Z Sui Xinbing X Yao Junlin J Xie Jiansheng J Jiang Liming L Zhou Yubin Y Pan Hongming H Han Weidong W

Cancer letters 20160120 2

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 ...[more]

PMID: 26803057

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Project description:Novel quinazolinone compounds have been studied in the field of drug discovery for a long time. Among their broad range of pharmacological effects, certain compounds effectively inhibit cancer cell proliferation. MJ?33 is a quinazolinone derivative with proposed anticancer activities that was synthesized in our laboratory. The present study aimed to evaluate the anticancer activity of MJ?33 in fluorouracil (5FU)?resistant colorectal cancer cells (HT?29/5FUR) and to investigate the underlying molecular mechanisms. The cell viability assay results indicated that HT?29/5FUR cell viability was inhibited by MJ?33 treatment in a concentration?dependent manner compared with the control group. The cellular morphological alterations observed following MJ?33 treatment indicated the occurrence of apoptosis and autophagy, as well as inhibition of cell proliferation in a time?dependent manner compared with the control group. The acridine orange, LysoTracker Red and LC3?green fluorescent protein staining results indicated that MJ?33 treatment significantly induced autophagy compared with the control group. The DAPI/TUNEL dual staining results demonstrated increased nuclear fragmentation and condensation following MJ?33 treatment compared with the control group. The Annexin V apoptosis assay and image cytometry analysis results demonstrated a significant increase in apoptotic cells following MJ?33 treatment compared with the control group. The western blotting results demonstrated markedly decreased Bcl?2, phosphorylated (p)?BAD, pro?caspase?9 and pro?caspase?3 expression levels, and notably increased cytochrome c and apoptotic peptidase activating factor 1 expression levels following MJ?33 treatment compared with the control group. Moreover, the expression levels of autophagy?related proteins, including autophagy related (ATG)?5, ATG?7, ATG?12, ATG?16, p62 and LC3?II, were increased following MJ?33 treatment compared with the control group. Furthermore, MJ?33?treated HT?29/5FUR cells displayed decreased expression levels of p?AKT and p?mTOR compared with control cells. The results suggested that MJ?33?induced apoptosis was mediated by AKT signaling, and subsequently modulated via the mitochondria?dependent signaling pathway. Therefore, the results suggested that suppression of AKT/mTOR activity triggered autophagy in the HT?29/5FUR cell line. In summary, the results indicated that MJ?33 inhibited HT?29/5FUR cell viability, and induced apoptosis and autophagy via the AKT/mTOR signaling pathway. The present study may provide novel insight into the anticancer effects and mechanisms underlying MJ?33 in 5FU?resistant colorectal cancer cells.

Dataset Information

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

Publications

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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