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

研究成果: Contribution to journalArticle査読

5 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号e0123076
ジャーナルPloS one
10
4
DOI
出版ステータス出版済み - 4 16 2015

All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)
  • 農業および生物科学(全般)
  • 一般

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