title: Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1.
abstract: 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.
authors: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Qiwei
authors: Q
authors: Li
authors: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Ming
authors: M
authors: Zhan
authors: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Wei
authors: W
authors: Chen
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Benpeng
authors: B
authors: Zhao
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Kai
authors: K
authors: Yang
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Jie
authors: J
authors: Yang
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Jing
authors: J
authors: Yi
authors: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
authors: Qihong
authors: Q
authors: Huang
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Man
authors: M
authors: Mohan
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Institutes of Medical Sciences, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors: Zhaoyuan
authors: Z
authors: Hou
authors: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Jian
authors: J
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D031223:Nasturtium / Q000737:chemistry; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C058305:phenethyl isothiocyanate; D005978:Glutathione; D002945:Cisplatin
keywords: Mcl-1; PEITC; biliary tract cancer; cisplatin; glutathionylation