Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1.
Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1.
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DOI：
10.18632/oncotarget.7171
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Li Q;Zhan M;Chen W;Zhao B;Yang K;Yang J;Yi J;Huang Q;Mohan M;Hou Z;Wang J
胆道癌是一种高度恶性的癌症。BTC对顺铂(CDDP)的应答率较低，因此迫切需要了解顺铂耐药的机制。在这里，我们表明，BTC细胞产生顺铂耐药，部分原因是髓系细胞白血病1(Mcl-1)上调。异硫氰酸苯乙酯(PEITC)是豆瓣菜中的一种天然化合物，可通过降解Mcl-1来增强顺铂的疗效。PEITC-CDDP联合治疗还可增加肿瘤干细胞样侧群(SP)细胞的凋亡率，抑制移植瘤生长，但无明显毒副作用。在体外，PEITC降低还原型谷胱甘肽(GSH)，导致GSH/氧化谷胱甘肽(GSSG)比值降低，增加Mcl-1的谷胱甘肽基化，导致Mcl-1蛋白酶体的快速降解。此外，我们还鉴定了Cys16和Cys286为Mcl-1谷胱甘肽基化位点，突变后得到了PEITC介导的抗降解Mcl-1蛋白。总之，我们首次在BTC细胞中证明了CDDP耐药与Mcl-1的部分相关，并且我们发现了一种新的机制，即PEITC可以通过谷胱甘肽依赖的Mcl-1降解来增强CDDP诱导的细胞凋亡。因此，我们的结果支持饮食摄入豆瓣菜可能有助于逆转BTC患者的顺铂抵抗。
Biliary tract cancer (BTC) is a highly malignant cancer. BTC exhibits a low response rate to cisplatin (CDDP) treatment, and therefore, an understanding of the mechanism of CDDP resistance is urgently needed. Here, we show that BTC cells develop CDDP resistance due, in part, to upregulation of myeloid cell leukemia 1 (Mcl-1). Phenylethyl isothiocyanate (PEITC), a natural compound found in watercress, could enhance the efficacy of CDDP by degrading Mcl-1. PEITC-CDDP co-treatment also increased the rate of apoptosis of cancer stem-like side population (SP) cells and inhibited xenograft tumor growth without obvious toxic effects. In vitro, PEITC decreased reduced glutathione (GSH), which resulted in decreased GSH/oxidized glutathione (GSSG) ratio and increased glutathionylation of Mcl-1, leading to rapid proteasomal degradation of Mcl-1. Furthermore, we identified Cys16 and Cys286 as Mcl-1 glutathionylation sites, and mutating them resulted in PEITC-mediated degradation resistant Mcl-1 protein. In conclusion, we demonstrate for the first time that CDDP resistance is partially associated with Mcl-1 in BTC cells and we identify a novel mechanism that PEITC can enhance CDDP-induced apoptosis via glutathionylation-dependent degradation of Mcl-1. Hence, our results provide support that dietary intake of watercress may help reverse CDDP resistance in BTC patients.