RT Journal Article
SR Electronic
T1 Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Enhances Antiproliferative Activity of 5′-Deoxy-5-Fluorouridine in Cancer Cells through Induction of Uridine Phosphorylase
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 854
OP 860
DO 10.1124/mol.109.056424
VO 76
IS 4
A1 Xingxing Kong
A1 Heng Fan
A1 Xiaojun Liu
A1 Rui Wang
A1 Jichao Liang
A1 Nishith Gupta
A1 Yong Chen
A1 Fude Fang
A1 Yongsheng Chang
YR 2009
UL http://molpharm.aspetjournals.org/content/76/4/854.abstract
AB Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is capable of coactivating 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 antineoplastic 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-1α, which induces the transcription and enzymatic activity of UPase in various cancer cells and thus augments their susceptibility to 5′-DFUR. PGC-1α-induced activation of UPase expression occurs at its transcription level that is mediated by an estrogen-related receptor (ERR) binding site (−1078 to −1070 base pairs) 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-1α-responsive element. Moreover, the inhibition of PGC-1α/ERRα-dependent signaling by 3-[4-(2,4-bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT790) compromises the ability of PGC-1α to induce the transcript of UPase, indicating PGC-1α-dependent and ERRα-mediated up-regulation of UPase. Finally, the overexpression of PGC-1α 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-1α 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-fluorouracil-based chemotherapy. © 2009 The American Society for Pharmacology and Experimental Therapeutics