title: Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis.
abstract: Prothymosin alpha (PTMA) is overexpressed in various human tumors, including hepatocellular carcinoma (HCC). The significance of PTMA overexpression and its underlying mechanism remain unclear. We show here that silencing PTMA sensitizes HCC cells to the kinase inhibitor sorafenib. In contrast, ectopic expression of PTMA induces cell resistance to the drug. While inhibitors targeting JNK, ERK or PI3K reduce PTMA expression, only ERK activation is suppressed by sorafenib. In addition, inhibition of ERK produces a dramatic decrease in both endogenous PTMA level and promoter activation. Ectopic expression of active MKK1/2 considerably induces PTMA expression. We also identify a sorafenib-responsive segment lying 1000-1500-bp upstream of the PTMA transcription start site and observe that it is controlled by c-Myc and ERK. Mutation in the PTMA promoter at the predicted c-Myc binding site and silencing of c-Myc both abrogate sorafenib's effect on PTMA transcription. We also find that silencing PTMA potentiates Bax translocation to mitochondria in response to sorafenib and this is associated with increased cytochrome c release from mitochondria and enhanced caspase-9 activation. These results indicate that PTMA is positively regulated by the oncoprotein c-Myc and protects HCC cells against sorafenib-induced cell death, thus identifying PTMA as a new target for chemotherapy against HCC.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, 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 333, Taiwan, Republic of China.
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Lu
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, 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 / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000633:toxicity; D010671:Phenylurea Compounds / Q000633:toxicity*; D011498:Protein Precursors / Q000502:physiology*; D000077157:Sorafenib; D013947:Thymosin / Q000031:analogs & derivatives* / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; D010671:Phenylurea Compounds; D011498:Protein Precursors; D014157:Transcription Factors; C040782:prothymosin alpha; D009536:Niacinamide; D013947:Thymosin; D000077157:Sorafenib
keywords: Apoptosis; Hepatocellular carcinoma; Prothymosin; Sorafenib.; c-Myc