Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy

SIMPLE SUMMARY: Urothelial bladder carcinoma entails significant health costs due to the high recurrence rates and poor response to standard cisplatin-based treatment. The glycolytic phenotype is a hallmark of proliferating cancer cells, but research is needed to validate the glycolysis-related proteins as prognostic and predictive biomarkers in the setting of bladder cancer. Here, we assessed the immunoexpression of several glycolysis-related biomarkers in bladder cancer tissues, demonstrating significant correlations with cancer aggressiveness and poor prognosis. Hexokinase 2 remained as an independent prognostic factor, which led us to further exploit the functional effects of the hexokinase 2 inhibitor 2-deoxy-D-glucose in “in vitro” and “in vivo” preclinical models of bladder cancer. The treatment impaired the classical aggressiveness features in the cancer cell lines and in the chick chorioallantoic membrane assay and also potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. Thus, we demonstrated the potential use of 2-deoxy-D-glucose in inhibiting bladder cancer progression and potentiating cisplatin effects. ABSTRACT: Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in “in vitro” and “in vivo” preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell’s viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance.