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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Resibufogenin 通过 RIP3 介导的坏死性凋亡抑制结直肠癌的生长和转移
DOI：
10.1186/s12967-018-1580-x
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发表时间：
2018-07-20
影响因子：
7.4
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Han Q;Ma Y;Wang H;Dai Y;Chen C;Liu Y;Jing L;Sun X
背景坏死性凋亡易感性可能是癌症的内在弱点。在此，我们报道了蟾蜍二烯内酯家族成员resibufogenin通过诱导体内坏死性凋亡来抑制结直肠癌（CRC）的生长和转移。方法将稳定表达增强型绿色荧光蛋白的SW480细胞异种移植到BALB/c-nu小鼠中观察肿瘤的生长。通过将MC38细胞注射到小鼠脾被膜下方观察肝转移。通过免疫组化、免疫荧光和蛋白质印迹法测定蛋白表达。结果综合体外结果表明，resibufogenin对CRC细胞具有抗增殖活性。 PI染色和透射电镜成像表明，脂蟾毒配基诱导的细胞死亡主要是通过坏死，这进一步被泛Caspase通用抑制剂z-VAD的无效性所证实。特别是，在受体相互作用蛋白激酶 3 (RIPK3) 敲除小鼠胚胎成纤维细胞中，resibufogenin 诱导的坏死基本上被消除。 RIP3依赖性坏死被归类为坏死性凋亡。 Resibufogenin 通过上调 RIP3 和磷酸化 Ser358 处的混合谱系激酶结构域样蛋白来触发坏死性凋亡。 Resibufogenin 还以 RIP3 依赖性方式激活 PYGL、GLUD1 和 GLUL 的表达。 Resibufogenin 通过诱导活性氧积累来发挥细胞毒性作用，活性氧可被 N-乙酰半胱氨酸中和。值得注意的是，resibufogenin 显着抑制脾脏植入引起的肝转移。该化合物的抗肿瘤作用可以通过RIP3敲低而消除。结论Resibufogenin通过RIP3介导的坏死性凋亡抑制CRC的生长和转移。
BackgroundNecroptotic 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.MethodsSW480 cells with stably expressing enhanced green fluorescence 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, immunofluorescence and western blot.ResultsConsolidated 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 confirmed by the ineffectiveness 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 fibroblasts. The RIP3-dependent necrosis has been classified 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 effect by inducing reactive oxygen species accumulation which can be neutralized byN-acetylcysteine. Remarkably, resibufogenin significantly suppresses liver-metastasis from spleen implantation. The anti-neoplastic effect of this compound can be abrogated by RIP3 knockdown.ConclusionResibufogenin suppresses growth and metastasis of CRC through RIP3-mediated necroptosis.
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影响因子：
18.4
作者：
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通讯作者：
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影响因子：
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