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.
Hepatocellular carcinoma (HCC) is one of the most frequent and fatal cancers encountered in the world. However, current pharmacological intervention does not provide a satisfactory cure, and therefore new treatments, are highly desirable. Targeting a protein or a protein activity that is present only in 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. HCC could be an ideal target for HK2 inhibition. First, systemic drug delivery leads to its accumulation in the liver and thus relatively low doses of HK2 inhibitor would be required. Second, since HK2 is expressed only in HCC cells its inhibition would selectively target only the cancer cells and not normal hepatocytes.
|Mehta, Manan M; Weinberg, Samuel E; Steinert, Elizabeth M et al. (2018) Hexokinase 2 is dispensable for T cell-dependent immunity. Cancer Metab 6:10|
|DeWaal, Dannielle; Nogueira, Veronique; Terry, Alexander R et al. (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446|
|Petit, Lolita; Ma, Shan; Cipi, Joris et al. (2018) Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa. Cell Rep 23:2629-2642|
|Nogueira, Veronique; Patra, Krushna C; Hay, Nissim (2018) Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation. Elife 7:|
|Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre et al. (2017) FGF-dependent metabolic control of vascular development. Nature 545:224-228|
|Hay, Nissim (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635-49|