Starvation Induced Autophagy Promotes The Progression of Bladder Cancer By LDHA Mediated Metabolic Reprogramming

Abstract Background: Aberrantly autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA), which are both related to malignant progression. But the regulatory relationship between autophagy and glycolytic metabolism remains unveiled. We imitated a starvation condition of tumor microenvironment and found significantly increased level of autophagy and aerobic glycolysis, which both regulated progression of BLCA cells. We further explored regulatory relationships and mechanisms between them.Methods: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels of BLCA cells under different treatment. Lactate and glucose concentration detection demonstrated changes on glycolysis. Expression of lactate dehydrogenase A (LDHA) were detected at transcriptional and translational levels, which were also silenced by small interfering RNA and effects on malignant progression further tested. Underlying mechanisms on signaling pathways were performed by western blot, immunofluorescence and immunoprecipitation assays.Results: Starvation induced autophagy, regulated glycolysis by up-regulating expression of LDHA and caused progressive changes in BLCA cells. Mechanically, after starved ubiquitination modification of Axin1 increased and combined with P62, further degraded by autophagy-lysosome pathway. Liberated β-catenin nuclear translocation increased, binding with LEF1/TCF4 and promotes LDHA transcriptional expression. Also, high expression of LDHA was observed in cancer tissues and positively related to progression.Conclusion: Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhances Axin1 degradation and β-catenin nuclear translocation in BLCA, which promotes transcriptional expression of LDHA and further malignant progression.