TY - JOUR
T1 - C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism
AU - Gao, Ping
AU - Tchernyshyov, Irina
AU - Chang, Tsung Cheng
AU - Lee, Yun Sil
AU - Kita, Kayoko
AU - Ochi, Takafumi
AU - Zeller, Karen I.
AU - De Marzo, Angelo M.
AU - Van Eyk, Jennifer E.
AU - Mendell, Joshua T.
AU - Dang, Chi V.
N1 - Funding Information:
Acknowledgements The authors want to thank L. Blosser and A. Tam for their help in flow cytometry analysis, and H. Y. Zhang for her help with statistical analysis. This work was partially supported by NIH Awards NHLBI NO1-HV-28180, NCI R01CA051497, NCI R01CA57341, NCI R01CA120185, NCI P50CA58236, Rita Allen Foundation, Leukemia and Lymphoma Society, and Sol Goldman Center for Pancreatic Cancer Research.
PY - 2009/4/9
Y1 - 2009/4/9
N2 - Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.
AB - Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.
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U2 - 10.1038/nature07823
DO - 10.1038/nature07823
M3 - Article
C2 - 19219026
AN - SCOPUS:64749116346
SN - 0028-0836
VL - 458
SP - 762
EP - 765
JO - Nature
JF - Nature
IS - 7239
ER -