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Modulation of Uridine Phosphorylase Gene Expression by Tumor Necrosis Factor- Enhances the Antiproliferative Activity of the Capecitabine Intermediate 5'-Deoxy-5-fluorouridine in Breast Cancer Cells

Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut (L.W., J.Z., G.P.); Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois (D.C., R.Y.); and Nevada Cancer Institute, Las Vegas, Nevada (G.P.)

Uridine phosphorylase (UPase) has been shown to play an important role in the antineoplastic activity of 5-fluorouracil (5-FU) and in the anabolism of its oral prodrug, capecitabine, through the conversion of 5'-deoxy-5-fluorouridine (5'-DFUR) into 5-FU. In this study, we investigated the effect of tumor necrosis factor- (TNF-) on UPase gene expression and 5'-DFUR antiproliferative activity and elucidated the involved signal transduction pathway. Our data indicate that TNF- significantly induced UPase mRNA expression and its enzymatic activity in EMT6 murine breast cancer cells, leading to an enhanced cytotoxicity of 5'-DFUR. This is further confirmed by an increased incorporation of 5'-DFUR-originated 5-FU nucleotides into nucleic acids. To clarify the mechanism of TNF--induced UPase expression, we first observed the effect of TNF- on the UPase promoter activity with a series of 5'-deleted promoter-luciferase constructs. Transient transfection analysis showed that the TNF--inductive pattern in EMT6 cells was consistent with the presence of a nuclear factor-B (NF-B) binding element (-1332/-1312 bp) in the UPase promoter region. Furthermore, electrophoretic mobility shift assays, supershift, and cotransfection assays revealed that the activation of p65 was responsible for UPase induction by TNF-. Finally, the induction of UPase by TNF- could be suppressed by PS-341, a NF-B inhibitor. In summary, TNF- efficiently induces UPase gene expression through a NF-B subunit p65-dependent pathway enhancing cell sensitivity to 5'-DFUR. The elucidation of this regulation mechanism may aid in the clinical use of 5-FU-based chemotherapy.

Address correspondence to: Dr. Giuseppe Pizzorno, Department of Internal Medicine (Oncology), Yale University School of Medicine, 333 Cedar Street, SHM I 220, New Haven, CT 06520. E-mail: giuseppe.pizzorno{at}yale.edu

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