This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhao, H.-Y. Articles by Akiyama, S.-i. Search for Related Content PubMed PubMed Citation Articles by Zhao, H.-Y. Articles by Akiyama, S.-i.

Molecular Basis for the Induction of an Angiogenesis Inhibitor, Thrombospondin-1, by 5-Fluorouracil

¹ Department of Molecular Oncology and ² Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan; ³ Personalized Medication Research Laboratory, Taiho Pharmaceutical Company, Ebisuno, Tokushima, Japan; ⁴ Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Fukuoka, Japan; and ⁵ Innovation Center for Medical Redox Navigation, Kyushu University, Maidashi, Higashi-Ku Fukuoka, Japan

Requests for reprints: Shin-ichi Akiyama, Department of Molecular Oncology, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. Phone: 81-99-275-5490; Fax: 81-99-265-9687; E-mail: akiyamas{at}m3.kufm.kagoshima-u.ac.jp.

Key Words: 5-fluorouracil • thrombospondin-1 • early growth response-1 • p38 MAPK pathway

5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in chemotherapy against various solid tumors. 5-FU dose-dependently increased the expression levels of intrinsic antiangiogenic factor thrombospondin-1 (TSP-1) in human colon carcinoma KM12C cells and human breast cancer MCF7 cells. We investigated the molecular basis for the induction of TSP-1 by 5-FU in KM12C cells. Promoter assays showed that the region with the Egr-1 binding site is critical for the induction of TSP-1 promoter activity by 5-FU. The binding of Egr-1 to the TSP-1 promoter was increased in KM12C cells treated with 5-FU. Immunofluorescence staining revealed that 5-FU significantly increased the level of Egr-1 in the nuclei of KM12C cells. The suppression of Egr-1 expression by small interfering RNA decreased the expression level of TSP-1. Furthermore, 5-FU induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27). Blockade of the p38 MAPK pathway by SB203580 remarkably inhibited the phosphorylation of HSP27 induced by 5-FU and decreased the induction of Egr-1 and TSP-1 by 5-FU in KM12C cells. These findings suggest that the p38 MAPK pathway plays a crucial role in the induction of Egr-1 by 5-FU and that induced Egr-1 augments TSP-1 promoter activity, with the subsequent production of TSP-1 mRNA and protein. [Cancer Res 2008;68(17):7035–41]