Project Summary Targeting a protein or a protein activity that is present only in hepatocellular carcinoma (HCC) cells and is required for HCC could be an ideal therapeutic approach that selectively targets HCC and spares normal hepatocytes. One such protein is hexokinase 2 (HK2) that catalyzes the first committed step in glucose metabolism. HK2 is perhaps the only glycolytic enzyme that is expressed in the cancer cells and not in their normal matching cells. HK2 is expressed only in embryonic liver and not in the adult liver. In the adult liver HK2 is ceased to be expressed and normal differentiated hepatocytes only express the low affinity hexokinase, glucokinase (GK), as an adaptation to liver function. However, HK2 is highly expressed in HCC cells while GK expression is suppressed. The highly glycolytic HCC cells are therefore dependent on HK2, establishing HK2 as an attractive selective target for HCC therapy. In a survey of 312 patient samples we found a strong correlation between high level of HK2 expression, dysplasia, and carcinoma regardless of the type or cause of HCC. Thus, despite the genetic heterogeneity of HCC, the induction of HK2 expression and the shift from GK to HK2 are common events in HCC. We found that systemic whole body deletion of HK2 in adult mice does not elicit adverse physiological consequences and is therapeutic for breast and lung cancers in mice. Because the only hexokinase expressed in HCC cells is HK2, it could be an ideal target for HCC therapy. The ultimate goals of this grant application are to understand the requirement of HK2 for the development of HCC and to examine the feasibility of HK2 inhibition for HCC therapy.
