Hexokinase II as a Potential Target of Apigenin Through the Induction of Apoptosis and Necroptosis in Malignant Mesothelioma

Background: Lactate-acclimated MSTO-211HAcT and H2452AcT malignant mesothelioma (MM) cells were previously found to tolerate gemcitabine more readily than their parental cells while remaining sensitive to apigenin. We examined whether changes in glucose metabolism and HKII contribute to the apigenin response. Methods: Apigenin was evaluated in monolayer and spheroid cultures and in a xenograft model; HKII was also silenced in the acclimated cells. Results: Apigenin reduced cell viability, p-AKT (Ser473), glycolysis-associated proteins including HKII, and mitochondrial electron transport chain proteins, while increasing p53 and markers of cell death. Tumor growth and selected metabolic proteins were reduced in the xenograft model. HKII silencing reduced cell viability and glucose utilization, lowered cellular ATP, altered mitochondrial membrane potential, and increased markers of apoptosis and necroptosis. Conclusions: HKII-associated metabolism contributes to survival of lactate-acclimated MM cells, and apigenin affects this metabolic phenotype. Direct targeting of HKII by apigenin and the complete mitochondrial apoptotic pathway require further study.