title: c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. pgao2@jhmi.edu
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Irina
authors.initials: I
authors.lastname: Tchernyshyov
authors.forename: Tsung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kita
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ochi
authors.forename: Karen I
authors.initials: KI
authors.lastname: Zeller
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
mesh_terms: 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*
chemical_list: D020413:3' Untranslated Regions; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D005972:Glutaminase