title: Uncoupling protein 2 mediates resistance to gemcitabine-induced apoptosis in hepatocellular carcinoma cell lines.
abstract: Oxidative stress induction is a common effector pathway for commonly used chemotherapeutic agents like gemcitabine (GEM) in hepatocellular carcinoma (HCC) patients. However, GEM alone or in combination with oxiplatin hardly renders any survival benefits to HCC patients. Mitochondrial uncoupling protein 2 (UCP2) is known to suppress mitochondrial reactive oxygen species (ROS) generation, thus mitigating oxidative stress-induced apoptosis. We demonstrate in the present study, using a panel of HCC cell lines that sensitivity to GEM in HCC well correlate with the endogenous level of UCP2 protein expression. Moreover, ectopic overexpression of UCP2 in a HCC cell line with low endogenous UCP2 expression, HLE, significantly decreased mitochondrial superoxide induction by the anti-cancer drug GEM. Conversely, UCP2 mRNA silencing by RNA interference in HCC cell lines with high endogenous UCP2 expression significantly enhanced GEM-induced mitochondrial superoxide generation and apoptosis. Cumulatively, our results suggest a critical role for mitochondrial uncoupling in GEM resistance in HCC cell lines. Hence, synergistic targeting of UCP2 in combination with other chemotherapeutic agents might be more potent in HCC patients.
authors.affiliation: Department of Hepatobiliary Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Guangsheng
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China jiahongdong1@163.com kesenxu@163.com.
authors.forename: Kesen
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250012, China Department of Hepatobiliary Surgery, Chinese General PLA Hospital, Beijing 100853, China jiahongdong1@163.com kesenxu@163.com.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Dong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D000093542:Gemcitabine
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: chemoresistance; gemcitabine; hepatocellular carcinoma (HCC); uncoupling protein 2 (UCP2)