ABERRANT GLYCOLYTIC METABOLISM OF CANCER-CELLS - A REMARKABLE COORDINATION OF GENETIC, TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND MUTATIONAL EVENTS THAT LEAD TO A CRITICAL ROLE FOR TYPE-II HEXOKINASE

For more than two-thirds of this century we have known that one of the most common and profound phenotypes of cancer cells is their propensi ty to utilize and catabolize glucose at high rates. This common bioche mical signature of many cancers, particularly those that are poorly di fferentiated and proliferate rapidly, has remained until recently a '' metabolic enigma.'' However, with many advances in the biological scie nces having been applied to this problem, cancer cells have begun to r eveal their molecular strategies in maintaining an aberrant metabolic behavior. Specifically, studies performed over the past two decades in our laboratory demonstrate that hexokinase, particularly the Type II isoform, plays a critical role in initiating and maintaining the high glucose catabolic rates of rapidly growing tumors. This enzyme convert s the incoming glucose to glucose-6-phosphate, the initial phosphoryla ted intermediate of the glycolytic pathway and an important precursor of many cellular ''building blocks.'' At the genetic level the tumor c ell adapts metabolically by first increasing the gene copy number of T ype II hexokinase. The enzyme's gene promoter, in turn, shows a wide p romiscuity toward the signal transduction cascades active within tumor cells. It is activated by glucose, insulin, low oxygen ''hypoxic'' co nditions, and phorbol esters, all of which enhance the rate of transcr iption. Also, the tumor cell uses the tumor suppressor p53, which is u sually modified by mutations to debilitate cell cycle controls, to fur ther activate hexokinase gene transcription. This results in both enha nced levels of the enzyme, which binds to mitochondrial porins thus ga ining preferential access to mitochondrially generated ATP, and in a d ecreased susceptibility to product inhibition and proteolytic degradat ion. Significantly, these multiple strategies all work together to ena ble tumor cells to develop a metabolic strategy compatible with rapid proliferation and prolonged survival.