Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming

Abstract

Hexokinases (HKs) convert hexose sugars to hexose-6-phosphate, thus trapping them inside cells to meet the synthetic and energetic demands. HKs participate in various standard and altered physiological processes, including cancer, primarily through the reprogramming of cellular metabolism. Four canonical HKs have been identified with different expression patterns across tissues. HKs 1–3 play a role in glucose utilization, whereas HK 4 (glucokinase, GCK) also acts as a glucose sensor. Recently, a novel fifth HK, hexokinase domain containing 1 (HKDC1), has been identified, which plays a role in whole-body glucose utilization and insulin sensitivity. Beyond the metabolic functions, HKDC1 is differentially expressed in many forms of human cancer. This review focuses on the role of HKs, particularly HKDC1, in metabolic reprogramming and cancer progression.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

“…Hexokinases carry out the phosphorylation of glucose and we wanted to learn if BKIDCs were dependent on a specific isoform of hexokinase (HK). Among five isoforms of hexokinases expressed in humans (HK1, HK2, HK3, GCK1/HK4, and HKDC1)(56), HK1 and HK2 are reportedly predominant in LNCaP cells(57). We used a CRISPR-Cas9 system to generate HK1 and HK2 knock-out (KO) LNCaP clones.…”

“…Multiple enzymatic isoforms can also perform overlapping functions, and metabolic flexibility can divert processes away from inhibited pathways. Mammals possess five HK isoenzymes, including HK1, HK2, HK3, HK4/GCK1, and HKDC1 with overlapping and specific tissue and cellular distribution patterns to fix glucose as the first step in glycolysis (56). Along with catalytic domains, HK1 and HK2 contain Nterminal motifs to interact with VDAC1 for association with mitochondria and the glucose-6-phosphate (G6P)-binding sties for feedback allosteric inhibition (56).…”

“…Mammals possess five HK isoenzymes, including HK1, HK2, HK3, HK4/GCK1, and HKDC1 with overlapping and specific tissue and cellular distribution patterns to fix glucose as the first step in glycolysis (56). Along with catalytic domains, HK1 and HK2 contain Nterminal motifs to interact with VDAC1 for association with mitochondria and the glucose-6-phosphate (G6P)-binding sties for feedback allosteric inhibition (56). HK2 is required for oncogenic transformation and progression of some cancers, but HK2 is minimally expressed in most adult tissues and its systemic deletion in adult mice does not lead to overt side effects (22).…”

Unraveling the Sweet Secrets of HCC: Glucometabolic Rewiring in Hepatocellular Carcinoma

“…HKs are the first rate-limiting enzymes involved in glycolysis, which phosphorylate glucose, thus trapping it inside the cells. 16 Five HK isozymes (HK1-4 and HKDC1) have been identified in humans with diverse tissue distribution and enzyme kinetics. HK4, commonly known as glucokinase, is the predominant HK isozyme of hepatocytes.…”

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

“…Subsequent studies found that HKDC1 is significantly upregulated and is a protumorigenic player in HCC and other cancers (11-14). Its impact on glucose update of cancer cells and the subcellular association with mitochondria-associated membranes have also been demonstrated (15). What remains unexplored are the potential differences of HKDC1 compared to the other upregulated HKs regarding their lineage specificity and metabolic activity in HCC since HCC is well known for its complex tumor microenvironment (TME) which consists of various cell types with different functions and metabolic needs.…”