DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis
| العنوان: | DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis |
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| المؤلفون: | Junji Yamauchi, Kazuko Aizawa, Kazuaki Nakamura, Akito Tanoue, Natsuko Kato, Kazuhiko Nakabayashi, Kenichiro Hata |
| المصدر: | PLoS ONE, Vol 8, Iss 1, p e54036 (2013) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Cancer Treatment, DNA Methyltransferase Inhibitor, lcsh:Medicine, Apoptosis, Cytidine, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Molecular cell biology, DNA (Cytosine-5-)-Methyltransferases, Phosphorylation, lcsh:Science, Multidisciplinary, Cell Death, Liver Neoplasms, Retinoblastoma protein, Hep G2 Cells, Oncology, Caspases, DNA methylation, Medicine, DNA modification, Research Article, Carcinoma, Hepatocellular, MAP Kinase Signaling System, Antineoplastic Agents, Biology, Cell Growth, Chemical Biology, Gastrointestinal Tumors, medicine, Humans, Protein kinase A, Cell Proliferation, Cyclin-dependent kinase 2, lcsh:R, Cancers and Neoplasms, Hepatocellular Carcinoma, Chemotherapy and Drug Treatment, DNA Methylation, Protein kinase R, Molecular biology, Zebularine, chemistry, biology.protein, Cancer research, lcsh:Q, Gene expression, Carcinogenesis |
| الوصف: | Hepatocellular carcinoma is one of the most common cancers worldwide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-(D)-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. We demonstrate that zebularine exhibits antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis, however, it has little effect on DNA methylation in HepG2 cells. On the other hand, zebularine treatment downregulated CDK2 and the phosphorylation of retinoblastoma protein (Rb), and upregulated p21(WAF/CIP1) and p53. We also found that zebularine treatment upregulated the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). These results suggest that the p44/42 MAPK pathway plays a role in zebularine-induced cell-cycle arrest by regulating the activity of p21(WAF/CIP1) and Rb. Furthermore, although the proapoptotic protein Bax levels were not affected, the antiapoptotic protein Bcl-2 level was downregulated with zebularine treatment. In addition, the data in the present study indicate that inhibition of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results suggest a novel mechanism of zebularine-induced cell growth arrest and apoptosis via a DNA methylation-independent pathway in hepatocellular carcinoma. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0fa9c517d8511a8fc2a2764d9e3e901bTest http://europepmc.org/articles/PMC3540068?pdf=renderTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0fa9c517d8511a8fc2a2764d9e3e901b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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