Hexokinase II and Its Major Partners: Role in Cancer Progression

Abstract

A key hallmark of many cancers, especially the most aggressive, has the capacity to metabolize glucose at an elevated rate, phenotype detected by clinically using positron emission tomography (PET). This phenotype provides cancer cells, includes those that participate in metastasis a different competitive edge over normal cells. After rapid entry of glucose into cancer cells on the glucose transporter, highly glycolytic phenotype is supported by hexokinase (primarily HK II) are highly expressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesize by the inner membrane located ATP synthase, to active sites on HK II. The large amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. Accelerated glucose metabolism is a common feature of cancer cells. Unlike normal cells which mainly metabolize glucose by using mitochondrial oxidative phosphorylation to generate ATP, cancer cells exhibit metabolic alterations by choosing aerobic glycolysis to convert glucose to lactate regardless of the presence of adequate oxygen. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) expressed at high levels in cancer cells, but only in a few number of normal adult tissues. Tumors during growth progression faces many challenges but amongst them major metabolic challenges are-how to fulfill bioenergetic and biosynthetic needs of increased cells due to proliferation and how to withstand environmental fluctuations in external nutrient and oxygen availability. An emerging theme in cancer biology is that many of the genes that can initiate tumorigenesis are intricately linked to metabolic regulation. Some metabolic enzymes in cancer have gained non-enzymatic functions to facilitate tumor adaptation and growth. Metabolic reprogramming of cancer cells promotes survival and proliferation with which it also tolerates stress and induces drug resistance. In this review, we considered the potential role of tumor initiator enzyme called Hexokinase II.