Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis
Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis
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DOI：
10.1186/s12967-018-1580-x
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xuegang Sun
中科院分区：
文献类型：
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作者：
Qinrui Han;Ye Ma;Hao Wang;Yu Dai;Chunhui Chen;Yawei Liu;Linlin Jing;Xuegang Sun
Background: Necroptotic susceptibility is probably an intrinsic weakness of cancer. Here, we report that resibufogenin, a member of bufadienolide family, suppresses the growth and metastasis of colorectal cancer (CRC) through induction of necroptosis in vivo..Methods: SW480 cells with stably expressing enhanced green fuorescence protein were xenografted to BALB/c-nu mice to observe the growth of tumors. Liver metastasis was observed by injection of MC38 cells beneath the splenic capsule of mice. Protein expression was determined by immunohistochemistry, immunofuorescence and western blot..Results: Consolidated in vitro results indicate that resibufogenin has anti-proliferative activity on CRC cells. PI staining and transmission electron microscope imaging suggest that the cell death induced by resibufogenin are mainly through necrosis, which is further confrmed by the inefectiveness of z-VAD, a pan-caspase general inhibitor. In particular, resibufogenin induced necrosis is substantially abrogated in receptor-interacting protein kinase 3 (RIPK3) knockout mouse embryo fbroblasts. The RIP3-dependent necrosis has been classifed as necroptosis. Resibufogenin triggeres necroptosis through upregulating RIP3 and phosphorylating mixed lineage kinase domain-like protein at Ser358. Resibufogenin also activates the expression of PYGL, GLUD1 and GLUL in a RIP3-dependent manner. Resibufogenin exerts cytotoxic efect by inducing reactive oxygen species accumulation which can be neutralized by N-acetylcysteine. Remarkably, resibufogenin signifcantly suppresses liver-metastasis from spleen implantation. The anti-neoplastic efect of this compound can be abrogated by RIP3 knockdown. .Conclusion: Resibufogenin suppresses growth and metastasis of CRC through RIP3-mediated necroptosis.
