title: Inhibition of JNK and prothymosin-alpha sensitizes hepatocellular carcinoma cells to cisplatin.
abstract: Cisplatin is a potent chemotherapeutic drug widely used for the treatment of human cancer. However, its efficacy against hepatocellular carcinoma (HCC) is poor for reasons that remain unclear. We show here that prothymosin-alpha (PTMA) is overexpressed in HCC cell lines. Silencing PTMA using short-hairpin RNA sensitizes HCC cells to cisplatin, while ectopic expression of PTMA induces cell resistance to the drug. Cisplatin inhibits both the JNK pathway and PTMA in a dose-dependent manner. Treatment with a JNK inhibitor also reduces PTMA protein stability and sensitizes HCC cells to cisplatin. Notably, the effects of PTMA silencing and JNK inhibition can be reversed by ectopic expression of PTMA. We show that PTMA silencing induces translocation of proapoptotic Bax to mitochondria and enhances cisplatin-induced cytochrome c release and caspase-9 activation. Conversely, ectopic expression of PTMA reverses these effects. Our results indicate that PTMA is positively regulated by JNK and protects HCC cells against cisplatin-induced cell death. The JNK/PTMA axis may thus represent a novel target for chemotherapy against HCC.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China.
authors.forename: Yi-Te
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Republic of China; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33302, Taiwan, Republic of China. Electronic address: cckchao@mail.cgu.edu.tw.
authors.forename: Chuck C-K
authors.initials: CC
authors.lastname: Chao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D053453:Caspase 9; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D045304:Cytochromes c; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008928:Mitochondria / Q000378:metabolism; D011498:Protein Precursors / Q000037:antagonists & inhibitors*; D021381:Protein Transport; D013947:Thymosin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011498:Protein Precursors; D051028:bcl-2-Associated X Protein; C040782:prothymosin alpha; D013947:Thymosin; D045304:Cytochromes c; D048670:MAP Kinase Kinase 4; D053453:Caspase 9; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Hepatocellular carcinoma; JNK; Prothymosin