論文 - 詳細
| RRC ID | 18684 |
|---|---|
| 著者 | Takezawa K, Okamoto I, Tsukioka S, Uchida J, Kiniwa M, Fukuoka M, Nakagawa K. |
| タイトル | Identification of thymidylate synthase as a potential therapeutic target for lung cancer. |
| ジャーナル | Br J Cancer |
| Abstract |
BACKGROUND:Thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidine, is an important chemotherapeutic target for malignant tumours including lung cancer. Although inhibition of TS has an antiproliferative effect in cancer cells, the precise mechanism of this effect has remained unclear. METHODS:We examined the effects of TS inhibition with an RNA interference-based approach. The effect of TS depletion on the growth of lung cancer cells was examined using colorimetric assay and flow cytometry. RESULTS:Measurement of the enzymatic activity of TS in 30 human lung cancer cell lines revealed that such activity differs among tumour histotypes. Almost complete elimination of TS activity by RNA interference resulted in inhibition of cell proliferation in all tested cell lines, suggestive of a pivotal role for TS in cell proliferation independent of the original level of enzyme activity. The antiproliferative effect of TS depletion was accompanied by arrest of cells in S phase of the cell cycle and the induction of caspase-dependent apoptosis as well as by changes in the expression levels of cyclin E and c-Myc. Moreover, TS depletion induced downregulation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP), and it seemed to activate the mitochondrial pathway of apoptosis. CONCLUSION:Our data provide insight into the biological relevance of TS as well as a basis for clinical development of TS-targeted therapy for lung cancer. |
| 巻・号 | 103(3) |
| ページ | 354-61 |
| 公開日 | 2010-7-27 |
| DOI | 10.1038/sj.bjc.6605793 |
| PII | 6605793 |
| PMID | 20628382 |
| PMC | PMC2920030 |
| MeSH | Adenocarcinoma / enzymology Adenocarcinoma / genetics Adenocarcinoma / pathology Apoptosis Carcinoma, Large Cell / enzymology Carcinoma, Large Cell / genetics Carcinoma, Large Cell / pathology Carcinoma, Small Cell / enzymology Carcinoma, Small Cell / genetics Carcinoma, Small Cell / pathology Carcinoma, Squamous Cell / enzymology Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / pathology Caspase 3 / metabolism Cell Cycle / genetics Cell Division / genetics Cell Line, Tumor Cyclin E / genetics Cytosol / metabolism Gene Deletion Gene Expression Regulation, Neoplastic Humans Immunoblotting Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology Lung Neoplasms / genetics Lung Neoplasms / pathology Mitochondria / metabolism Proto-Oncogene Proteins c-myc / genetics RNA Interference S Phase / genetics Thymidylate Synthase / antagonists & inhibitors Thymidylate Synthase / deficiency Thymidylate Synthase / genetics* Thymidylate Synthase / metabolism |
| IF | 5.791 |
| 引用数 | 26 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | Lu-135(RCB0468) Lu-134-B(RCB0467) |