Dynamic modulation of Thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells

Kentaro Wakasa, Rumi Kawabata, Seiki Nakao, Hiroyoshi Hattori, Kenichi Taguchi, Junji Uchida, Takeharu Yamanaka, Yoshihiko Maehara, Masakazu Fukushima, Shinya Oda

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.

Original languageEnglish
Article numbere0123076
JournalPloS one
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 16 2015

Fingerprint

thymidylate synthase
fluorouracil
Thymidylate Synthase
colorectal neoplasms
Gene expression
Fluorouracil
Colorectal Neoplasms
Cells
Modulation
Gene Expression
gene expression
Biomarkers
biomarkers
Chemotherapy
drug therapy
neoplasms
Drug Therapy
Neoplasms
doxycycline
Doxycycline

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wakasa, K., Kawabata, R., Nakao, S., Hattori, H., Taguchi, K., Uchida, J., ... Oda, S. (2015). Dynamic modulation of Thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells. PloS one, 10(4), [e0123076]. https://doi.org/10.1371/journal.pone.0123076

Dynamic modulation of Thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells. / Wakasa, Kentaro; Kawabata, Rumi; Nakao, Seiki; Hattori, Hiroyoshi; Taguchi, Kenichi; Uchida, Junji; Yamanaka, Takeharu; Maehara, Yoshihiko; Fukushima, Masakazu; Oda, Shinya.

In: PloS one, Vol. 10, No. 4, e0123076, 16.04.2015.

Research output: Contribution to journalArticle

Wakasa, K, Kawabata, R, Nakao, S, Hattori, H, Taguchi, K, Uchida, J, Yamanaka, T, Maehara, Y, Fukushima, M & Oda, S 2015, 'Dynamic modulation of Thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells', PloS one, vol. 10, no. 4, e0123076. https://doi.org/10.1371/journal.pone.0123076
Wakasa, Kentaro ; Kawabata, Rumi ; Nakao, Seiki ; Hattori, Hiroyoshi ; Taguchi, Kenichi ; Uchida, Junji ; Yamanaka, Takeharu ; Maehara, Yoshihiko ; Fukushima, Masakazu ; Oda, Shinya. / Dynamic modulation of Thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells. In: PloS one. 2015 ; Vol. 10, No. 4.
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