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

Abstract 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 conditio...

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Autores principales:	Tinghao Li, Hang Tong, Hubin Yin, Yi Luo, Junlong Zhu, Zijia Qin, Siwen Yin, Weiyang He
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Bladder cancer Autophagy Glycolysis LDHA Wnt/β-catenin signalling Axin1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/32fd0edc7c904c63a8ca911fb8994560
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spelling	oai:doaj.org-article:32fd0edc7c904c63a8ca911fb89945602021-11-14T12:37:40ZStarvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming10.1186/s12935-021-02303-11475-2867https://doaj.org/article/32fd0edc7c904c63a8ca911fb89945602021-11-01T00:00:00Zhttps://doi.org/10.1186/s12935-021-02303-1https://doaj.org/toc/1475-2867Abstract 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 with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression. Conclusion Our 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.Tinghao LiHang TongHubin YinYi LuoJunlong ZhuZijia QinSiwen YinWeiyang HeBMCarticleBladder cancerAutophagyGlycolysisLDHAWnt/β-catenin signallingAxin1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCancer Cell International, Vol 21, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Bladder cancer Autophagy Glycolysis LDHA Wnt/β-catenin signalling Axin1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Bladder cancer Autophagy Glycolysis LDHA Wnt/β-catenin signalling Axin1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Tinghao Li Hang Tong Hubin Yin Yi Luo Junlong Zhu Zijia Qin Siwen Yin Weiyang He Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
description	Abstract 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 with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression. Conclusion Our 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.
format	article
author	Tinghao Li Hang Tong Hubin Yin Yi Luo Junlong Zhu Zijia Qin Siwen Yin Weiyang He
author_facet	Tinghao Li Hang Tong Hubin Yin Yi Luo Junlong Zhu Zijia Qin Siwen Yin Weiyang He
author_sort	Tinghao Li
title	Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
title_short	Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
title_full	Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
title_fullStr	Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
title_full_unstemmed	Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming
title_sort	starvation induced autophagy promotes the progression of bladder cancer by ldha mediated metabolic reprogramming
publisher	BMC
publishDate	2021
url	https://doaj.org/article/32fd0edc7c904c63a8ca911fb8994560
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Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

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