Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

Hexokinases are a family of ubiquitous exose-phosphorylating enzymes that prime glucose for intracellular utilization. Hexokinase 2 (HK2) is the most active isozyme of the family, mainly expressed in insulin-sensitive tissues. HK2 induction in most neoplastic cells contributes to their metabolic rewiring towards aerobic glycolysis, and its genetic ablation inhibits malignant growth in mouse models. HK2 can dock to mitochondria, where it performs additional functions in autophagy regulation and cell death inhibition that are independent of its enzymatic activity. The recent definition of HK2 localization to contact points between mitochondria and endoplasmic reticulum called Mitochondria Associated Membranes (MAMs) has unveiled a novel HK2 role in regulating intracellular Ca2+ fluxes. Here, we propose that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways. Disrupting these functions by targeting HK2 subcellular localization can constitute a promising anti-tumor strategy.

Automated summary

Hexokinases, particularly Hexokinase 2 (HK2), play a critical role in glucose metabolism and are highly expressed in insulin-sensitive tissues and neoplastic cells. In addition to its enzymatic activity, HK2 can regulate autophagy and cell death, as well as intracellular Ca2+ fluxes, at the mitochondria-associated membranes (MAMs). Targeting HK2 subcellular localization in MAMs may offer a promising anti-tumor strategy by disrupting its functions in metabolic and survival pathways.