| Title | Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1 alpha enhances anti-proliferative activity of 5'-Deoxy-5-Fluorouridine in cancer cells through induction of Uridine Phosphorylase. | | Author(s) | Kong X, Fan H, Liu X, Wang R, Liang J, Gupta N, Chen Y, Fang F, Chang Y | | Institution | National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences. | | Source | Mol Pharmacol 2009 Jul 14. | | Abstract | PGC-1alpha is capable of co-activating several nuclear receptors and transcription factors that participate in the regulation of multiple metabolic processes including gluconeogenesis, mitochondrial biogenesis and adaptive thermogenesis. Uridine phosphorylase (UPase) catalyzes the reversible conversion of uridine into uracil and contributes to the anti-neoplastic activity of 5'-Deoxy-5-fluorouridine (5'-DFUR) and homeostasis of uridine levels in plasma and tissues. This study demonstrates uridine phosphorylase as a novel target gene of PGC-1alpha, which induces the transcription and enzymatic activity of UPase in various cancer cells, and thus, augments their susceptibility to 5'-DFUR. PGC-1alpha-induced activation of UPase expression occurs at its transcription level that is mediated by an estrogen-related receptor (ERR) binding site (-1078 to -1070 bp) mapped in the promoter region of UPase gene. Our mutational studies using luciferase reporter construct together with electrophoretic mobility shift assays confirm the binding of ERR to PGC-1alpha responsive element. Moreover, the inhibition of PGC-1alpha/ERRalpha-dependent signaling by XCT790 compromises the ability of PGC-1alpha to induce the transcript of UPase indicating PGC-1alpha-dependent and ERRalpha-mediated upregulation of UPase. Finally, the over-expression of PGC-1alpha sensitizes breast and colon cancer cells to growth inhibition by 5'-DFUR presumably by inducing apoptosis in tumor cells, and XCT790 can inhibit the process. Taken together, our results corroborate the regulatory function of PGC-1alpha in uridine homeostasis and imply its links with the energy metabolism. The mechanistic elucidation of this association between both cellular pathways should advance the clinical use of 5-FU-based chemotherapy. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19602572 |
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