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

Cancer Cell International

Hubin Yin¹  Siwen Yin¹  Yi Luo¹  Zijia Qin¹  Tinghao Li²  Junlong Zhu²  Hang Tong²  Weiyang He³ 

[1] The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China;Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, 400016, Chongqing, People’s Republic of China;

关键词: Bladder cancer;    Autophagy;    Glycolysis;    LDHA;    Wnt/β-catenin signalling;    Axin1;   

DOI  :  10.1186/s12935-021-02303-1

来源: Springer

【 摘 要 】

BackgroundAberrant 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.MethodsWe 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.ResultsStarvation 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 with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression.ConclusionOur study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhancing Axin1 degradation and β-catenin nuclear translocation in BLCA, which promotes the transcriptional expression of LDHA and further malignant progression.

【 授权许可】

CC BY