AKT1/HK2 Axis-mediated Glucose Metabolism: A Novel Therapeutic Target of Sulforaphane in Bladder Cancer

Scope Metabolic disorder is a pivotal hallmark of cancer cells. Sulforaphane (SFN) is reported to improve lipid metabolism. However, the effect of SFN on glucose metabolism in bladder cancer remains unclear. Hence, the effect and underling mechanism is investigated. Methods and Results Biological samples from bladder cancer patients are collected, and also investigated using N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder cancer mice and bladder cancer cell lines. A novel glucose transport aberrant-independent aerobic glycolysis is found in bladder cancer patients, and the lower malignancy tissues have the more obvious abnormality. SFN strongly downregulates ATP production by inhibiting glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). Both in vitro cell culture and in bladder tumor mice, SFN weaken the glycolytic flux by suppressing multiple metabolic enzymes, including hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH). Moreover, SFN decreases the level of AKT1 and p-AKT (ser473), especially in low-invasive UMUC3 cells. The downregulation of ATP and HK2 by SFN is both reversed by AKT1 overexpression. Conclusions SFN downregulates the unique glucose transport aberrant-independent aerobic glycolysis existed in bladder cancer via blocking the AKT1/HK2 axis and PDH expression.

Automated summary

Sulforaphane (SFN) reduces ATP production in bladder cancer cells by inhibiting glycolysis and mitochondrial oxidative phosphorylation. SFN weakens glycolytic flux by suppressing metabolic enzymes such as hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH). Additionally, SFN downregulates the unique glucose transport aberrant-independent aerobic glycolysis in bladder cancer through the AKT1/HK2 axis and PDH expression.