Identification of thymidylate synthase as a potential therapeutic target for lung cancer

K. Takezawa, Isamu Okamoto, S. Tsukioka, J. Uchida, M. Kiniwa, M. Fukuoka, K. Nakagawa

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)354-361
Number of pages8
JournalBritish journal of cancer
Volume103
Issue number3
DOIs
Publication statusPublished - Jul 27 2010

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Thymidylate Synthase
Lung Neoplasms
Therapeutics
RNA Interference
X-Linked Inhibitor of Apoptosis Protein
Cell Proliferation
Apoptosis
Cell Line
Cyclin E
Neoplasms
Enzymes
Caspases
S Phase
Thymidine
Cell Cycle
Flow Cytometry
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Identification of thymidylate synthase as a potential therapeutic target for lung cancer. / Takezawa, K.; Okamoto, Isamu; Tsukioka, S.; Uchida, J.; Kiniwa, M.; Fukuoka, M.; Nakagawa, K.

In: British journal of cancer, Vol. 103, No. 3, 27.07.2010, p. 354-361.

Research output: Contribution to journalArticle

Takezawa, K, Okamoto, I, Tsukioka, S, Uchida, J, Kiniwa, M, Fukuoka, M & Nakagawa, K 2010, 'Identification of thymidylate synthase as a potential therapeutic target for lung cancer', British journal of cancer, vol. 103, no. 3, pp. 354-361. https://doi.org/10.1038/sj.bjc.6605793
Takezawa, K. ; Okamoto, Isamu ; Tsukioka, S. ; Uchida, J. ; Kiniwa, M. ; Fukuoka, M. ; Nakagawa, K. / Identification of thymidylate synthase as a potential therapeutic target for lung cancer. In: British journal of cancer. 2010 ; Vol. 103, No. 3. pp. 354-361.
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