Hexokinases in cancer and other pathologies

Abstract

Glucose metabolism is indispensable for cell growth and survival. Hexokinases play pivotal roles in glucose metabolism through canonical functions of hexokinases as well as in immune response, cell stemness, autophagy, and other cellular activities through noncanonical functions. The aberrant regulation of hexokinases contributes to the development and progression of pathologies, including cancer and immune diseases.

Keywords: Cancer; Glucose metabolism; Glycolysis; Hexokinase; Immune diseases; Protein kinase.

Fig. 1

Schematic representation of the sequence and functional domains of hexokinases. The red color tubes represent the kinase lobes that have the activity to phosphorylate glucose. The gray color lobes have no catalytic activity. MLS, mitochondrial localization sequence.

Fig. 2

Roles of hexokinases in different cellular activities. Hexokinases are involved in immune responses, cell stemness, cell survival and autophagy, DNA damage response, redox homeostasis, cell proliferation, and tumor invasion and migration through canonical and noncanonical functions.

Fig. 3

Noncanonical functions of HK2. Mitochondria-localized HK2 inhibits apoptosis by preventing the binding of Bax to the mitochondria. High level of G-6-P releases HK2 from the mitochondria to the cytosol, where it acts as a protein kinase to phosphorylate IκBα and consequently activates NF-κB-mediated CD274 transcription and tumor immune evasion. Cytosolic HK2 interacts with CD133 to enhance CD133 stability and promote tumor cell stemness, and interacts with and inhibits mTORC1 to induce autophagy. Bacteria-derived NAG also binds to HK2 and promotes its release from the mitochondria and activation of NLRP3 inflammasome.