Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) 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-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 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-1alpha-responsive
element. Moreover, the inhibition of PGC-1alpha/
ERRalpha-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-1alpha to induce the transcript of UPase, indicating PGC-1alpha-dependent and
ERRalpha-mediated up-regulation of UPase. Finally, the overexpression 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-fluorouracil-based
chemotherapy.