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.

Keywords: HKDC1; cancer metabolism; glucose metabolism; hexokinases; metabolic reprogramming.

Figure 1

Schematic representation of the functional domains of the five hexokinase isoforms. The rust-colored cylinders represent domains with catalytic activity, and the blue cylinders have no catalytic activity. Both cylinders in HKDC1 are gray colored because this isoform has very low kinase activity. MLS = mitochondrial localization sequence (red-colored cylinder). Numbers represent amino acid sequences adapted from Uniprot.org.

Figure 2

Illustration of the delivery of glucose to membrane-bound HKs in malignant cells. Illustration of the glucose delivery to HKs 1, 2, and HKDC1 bound to the outer mitochondrial membrane (OMM) and metabolic fates of the glucose-6-phosphate (G6P) formed thereof within a malignant cell. Glucose transport across the plasma membrane by glucose transporters is phosphorylated by HKs (HK1, HK2, or HKDC1) bound to a voltage-dependent anion channel (VDAC) located on the outer mitochondrial membrane. VDAC allows direct access of ATP generated by the ATP synthase within the mitochondria to the HKs, which can be transported across the inner-mitochondrial membrane by the adenine nucleotide translocator. To maintain malignant cells’ highly glycolytic metabolic flux, the product G6P is rapidly distributed across key metabolic routes (see thick green arrows). The primary metabolic routes for G6P are either entry into the pentose-phosphate pathway for biosynthesis of nucleic acid precursors or conversion to pyruvate and lactate through glycolysis. In cancer cells, most lactate is transported out of the cells with the aid of lactate transporters. In contrast, small amounts of pyruvate are transported to mitochondria through the pyruvate transporters to supply intermediates to the tricarboxylic acid (TCA) cycle (thin red arrows). Citrate transporters transport citrate produced in the TCA cycle to aid in synthesizing membrane components such as phospholipids and cholesterol, essential for tumor cell proliferation. * Novel hexokinase, HKDC1, with roles still unknown.

Figure 3

Schematic representation of the effects of HKDC1 over-expression in cancer cells. The cell membrane glucose transporters (GLUT 1/3) mediate the glucose uptake, which is degraded to pyruvate by glycolysis. Upregulation of HKDC1 (and other HKs) in many cancer types leads to enhanced generation of glycolytic intermediate, which functions as precursors for numerous metabolic pathways necessary for the biosynthesis of cellular components; pentose phosphate pathway (marked with thick red arrows), cholesterol biosynthesis, and fatty acid biosynthesis. Notably, HKDC1 upregulation leads to an increase in HKDC1-mitochondrial binding, which is responsible for the maintenance of glycolysis and TCA cycle and contributes to unabated cell proliferation through the aversion of apoptosis and endoplasmic reticulum (ER)-mediated stress response mechanisms by reducing the number of physical contact points between ER and mitochondria.