, Volume 29, Issue 4, pp 345-354

Oncogenes in Tumor Metabolism, Tumorigenesis, and Apoptosis

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Abstract

The ability of cancer cells to overproduce lactic acid aerobically was recognized by Warburg about seven decades ago, although its molecular basis has been elusive. Increases in glucose transport and hexokinase activity in cancer cells appear to account for the increased flux of glucose through the cancer cells. Herein we review current findings indicating that the c-Myc oncogenic transcription factor and hypoxia-inducible factor 1 (HIF-1) are able to bind the lactate dehydrogenase A promoter cis acting elements, which resemble the core carbohydrate response element (ChoRE), CACGTG. These and other observations suggest that the normal cell responds physiologically to changes in oxygen tension or the availability of glucose by altering glycolysis through the ChoRE, which hypothetically binds c-Myc, HIF-1, or related factors. The neoplastic cell is hypothesized to augment glycolysis by activation of ChoRE/ HIF-1 sites through direct interaction with c-Myc or through activation of HIF-1 or HIF-1 -like activity. We hypothesize that oncogene products either stimulate HIF-1 and related factors or, in the case of c-Myc, directly activate hypoxia/glucose responsive elements in glycolytic enzyme genes to increase the ability of cancer cells to undergo aerobic glycolysis.