Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis

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, ecto...

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Bibliographic Details
Published in:Biochemical pharmacology 2015-01, Vol.93 (1), p.110-124
Main Authors: Lin, Yi-Te, Lu, Hsing-Pang, Chao, Chuck C.-K.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - toxicity
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
c-Myc
Carcinoma, Hepatocellular - metabolism
DNA-Binding Proteins - physiology
Dose-Response Relationship, Drug
Hepatocellular carcinoma
Humans
Liver Neoplasms - metabolism
Niacinamide - analogs & derivatives
Niacinamide - toxicity
Phenylurea Compounds - toxicity
Protein Precursors - physiology
Prothymosin
Sorafenib
Thymosin - analogs & derivatives
Thymosin - physiology
Transcription Factors - physiology
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Summary: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.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2014.10.012