C-MYC TRANSACTIVATION OF LDH-A - IMPLICATIONS FOR TUMOR METABOLISM AND GROWTH

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; how ever, its molecular basis has remained elusive, The lactate dehydrogen ase-A gene (LDH-A), whose product participates in normal anaerobic gly colysis and Is frequently increased in human cancers, was identified a s a c-Myc-responsive gene. Stably transfected Rat1a fibroblasts that o verexpress LDH-A alone or those transformed c-Myc overproduce lactic a cid, LDH-A overexpression is required for c-Myc-mediated transformatio n because lowering its level through antisense LDH-A expression reduce s soft agar clonogenicity of c-Myc-transformed Rat1a fibroblasts, c-My c-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 hypoxi c internal microenvironment. Our studies have linked c-Myc to the indu ction of LDH-A, whose expression increases lactate production and is n ecessary for c-Myc-mediated transformation.