Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis
Autor: | Yi-Te Lin, Hsing-Pang Lu, Chuck C.-K. Chao |
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Rok vydání: | 2014 |
Předmět: |
Sorafenib
MAPK/ERK pathway Niacinamide Carcinoma Hepatocellular Antineoplastic Agents Apoptosis Biology Prothymosin Alpha Biochemistry Small hairpin RNA medicine Gene silencing Humans Protein Precursors neoplasms PI3K/AKT/mTOR pathway Pharmacology Dose-Response Relationship Drug Phenylurea Compounds Liver Neoplasms digestive system diseases DNA-Binding Proteins Thymosin Cancer research Ectopic expression medicine.drug Transcription Factors |
Zdroj: | Biochemical pharmacology. 93(1) |
ISSN: | 1873-2968 |
Popis: | 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. |
Databáze: | OpenAIRE |
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