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.
Highlights
Biliary tract cancer (BTC) refers to a group of cancers of the biliary tract, including gallbladder cancer, cholangiocarcinoma of intrahepatic and extrahepatic bile ducts, and cancers of the ampulla and papilla of Vater [1]
CDDP-based chemotherapy is an important treatment regimen used in the clinical management of BTC, but the mechanisms for CDDP resistance are not entirely clear
Cancer cells may become resistant to platinum-based drugs through multiple mechanisms, such as an increased ability to repair DNA damage caused by platinum, neutralization of platinum toxicity, blocking platinum entry into the nucleus, an increase in drug export and so on [11, 20,21,22,23,24]
Summary
Biliary tract cancer (BTC) refers to a group of cancers of the biliary tract, including gallbladder cancer, cholangiocarcinoma of intrahepatic and extrahepatic bile ducts, and cancers of the ampulla and papilla of Vater [1]. BTC is a common form of cancer in East Asia and Latin America [2, 3] and surgical resection is the only curative treatment. Most patients are diagnosed with advanced-stage disease, making them ineligible for complete surgical resection. The prognosis for patients with advanced BTC is very poor, and most survive for less than a year after diagnosis. Cisplatin (CDDP) based chemotherapy is widely used to treat patients with advanced BTC [4]. The mechanism of CDDP resistance in BTC cells is poorly understood. Investigation into the mechanism of CDDP resistance and strategies to alleviate the CDDP resistance are urgently needed
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