Peroxisome proliferator-activated receptor gamma coactivator-1alpha enhances antiproliferative activity of 5'-deoxy-5-fluorouridine in cancer cells through induction of uridine phosphorylase.
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.
Kong
Xingxing
X
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Fan
Heng
H
Liu
Xiaojun
X
Wang
Rui
R
Liang
Jichao
J
Gupta
Nishith
N
Chen
Yong
Y
Fang
Fude
F
Chang
Yongsheng
Y
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004790:Enzyme Induction; D005467:Floxuridine / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014543:Uridine Phosphorylase / Q000096:biosynthesis*; D000097983:ERRalpha Estrogen-Related Receptor
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D005467:Floxuridine; D011960:Receptors, Estrogen; D014157:Transcription Factors; D014543:Uridine Phosphorylase; D000097983:ERRalpha Estrogen-Related Receptor; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C025034:doxifluridine