Hexokinase 2 nonmetabolic function-mediated phosphorylation of IκBα enhances pancreatic ductal adenocarcinoma progression

Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates I kappa B alpha at T291 in PDAC cells, activating NF-kappa B, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity-promoted activation of NF-kappa B promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment. HK2-mediated phosphorylation of I kappa B alpha at T291 in PDAC cells leads to I kappa B alpha degradation and subsequent activation of NF-kappa B for the upregulation of downstream target transcription. HK2 nonmetabolic activity-promoted activation of NF-kappa B stimulates the proliferation, migration, and invasion of PDAC cells.image