title: Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS.
abstract: The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.
authors.affiliation: Department of Hepatobiliary & Pancreat Surgery, The Second Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Hepatobiliary & Pancreat Surgery, The Second Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
authors.forename: Jiyao
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Luyan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary & Pancreat Surgery, The Second Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D002738:Chloroquine; D002945:Cisplatin