Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

作者：Tinghao Li, Hang Tong, Hubin Yin, Yi Luo, Junlong Zhu, Zijia Qin, Siwen Yin, Weiyang He · 发表于：Cancer Cell International · 年份：2021 · DOI：10.1186/s12935-021-02303-1 · 被引用次数：49 · 研究领域：Autophagy in Disease and Therapy、Cancer, Hypoxia, and Metabolism、Bladder and Urothelial Cancer Treatments

BACKGROUND: Aberrant autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA) and are both related to malignant progression. However, the regulatory relationship between autophagy and glycolytic metabolism remains largely unknown. We imitated starvation conditions in the tumour microenvironment and found significantly increased levels of autophagy and aerobic glycolysis, which both regulated the progression of BLCA cells. We further explored the regulatory relationships and mechanisms between them. METHODS: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels in BLCA cells under different treatments. Lactate and glucose concentration detection demonstrated changes in glycolysis. The expression of lactate dehydrogenase A (LDHA) was detected at the transcriptional and translational levels and was also silenced by small interfering RNA, and the effects on malignant progression were further tested. The underlying mechanisms of signalling pathways were evaluated by western blot, immunofluorescence and immunoprecipitation assays. RESULTS: Starvation induced autophagy, regulated glycolysis by upregulating the expression of LDHA and caused progressive changes in BLCA cells. Mechanistically, after starvation, the ubiquitination modification of Axin1 increased, and Axin1 combined with P62 was further degraded by the autophagy-lysosome pathway. Liberated β-catenin nuclear translocation increased, binding...