c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
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.
Gao
Ping
P
Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. pgao2@jhmi.edu
Tchernyshyov
Irina
I
Chang
Tsung-Cheng
TC
Lee
Yun-Sil
YS
Kita
Kayoko
K
Ochi
Takafumi
T
Zeller
Karen I
KI
De Marzo
Angelo M
AM
Van Eyk
Jennifer E
JE
Mendell
Joshua T
JT
Dang
Chi V
CV
D020413:3' Untranslated Regions / Q000378:metabolism; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D005972:Glutaminase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
D020413:3' Untranslated Regions; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D005972:Glutaminase