Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells.
Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells.
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DOI：
10.18632/oncotarget.11147
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Oh SC
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文献类型：
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作者：
Park SH;Lee DH;Kim JL;Kim BR;Na YJ;Jo MJ;Jeong YA;Lee SY;Lee SI;Lee YY;Oh SC
二甲双胍是一种具有良好抗癌潜力的抗糖尿病药物。在这项研究中，我们发现亚毒性剂量的二甲双胍能有效地增强人结直肠癌细胞对肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的敏感性，从而诱导细胞凋亡。单独应用二甲双胍不能诱导大肠癌细胞的凋亡，但显著增强TRAIL诱导的大肠癌细胞的凋亡。经二甲双胍和TRAIL处理的大肠癌细胞显示caspase激活的内在和外在途径均被激活。我们试图阐明其可能的机制，发现二甲双胍可显著降低结直肠癌细胞中髓系白血病细胞白血病1(Mcl-1)的蛋白水平，并且过表达Mcl-1可抑制二甲双胍和/或TRAIL诱导的细胞死亡。进一步的实验表明，二甲双胍不影响Mcl-1的mRNA水平，但增加了Mcl-1蛋白酶体的降解和蛋白质的稳定性。Mule基因敲除后，Mcl-1多泛素化水平显著降低。二甲双胍引起Noxa与Mcl-1的解离，使含有BH3的泛素连接酶Mule结合，Mcl-1泛素化和降解。二甲双胍诱导Mcl-1的降解需要E3连接酶Mule，它负责Mcl-1的多泛素化。我们的研究是首次报道二甲双胍通过NOXA增强TRAIL诱导的细胞凋亡，并促进Mcl-1与Mule之间的相互作用，从而影响Mcl-1的泛素化。
Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.