title: c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
abstract: Cancer cells are able to overproduce lactic acid aerobically, whereas normal cells undergo anaerobic glycolysis only when deprived of oxygen. Tumor aerobic glycolysis was recognized about seven decades ago; however, its molecular basis has remained elusive. The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene. Stably transfected Rat1a fibroblasts that overexpress LDH-A alone or those transformed by c-Myc overproduce lactic acid. LDH-A overexpression is required for c-Myc-mediated transformation because lowering its level through antisense LDH-A expression reduces soft agar clonogenicity of c-Myc-transformed Rat1a fibroblasts, c-Myc-transformed human lymphoblastoid cells, and Burkitt lymphoma cells. Although antisense expression of LDH-A did not affect the growth of c-Myc-transformed fibroblasts adherent to culture dishes under normoxic conditions, the growth of these adherent cells in hypoxia was reduced. These observations suggest that an increased LDH-A level is required for the growth of a transformed spheroid cell mass, which has a hypoxic internal microenvironment. Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation.
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: H
authors.initials: H
authors.lastname: Shim
authors.forename: C
authors.initials: C
authors.lastname: Dolde
authors.forename: B C
authors.initials: BC
authors.lastname: Lewis
authors.forename: C S
authors.initials: CS
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Dang
authors.forename: R A
authors.initials: RA
authors.lastname: Jungmann
authors.forename: R
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: C V
authors.initials: CV
authors.lastname: Dang
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D007770:L-Lactate Dehydrogenase