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AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

ABSTRACT: AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the ?1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPK? in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1? (HIF-1?), as silencing HIF-1? reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPK? signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.

SUBMITTER: Faubert B

PROVIDER: S-EPMC3545102 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

Faubert Brandon B Boily Gino G Izreig Said S Griss Takla T Samborska Bozena B Dong Zhifeng Z Dupuy Fanny F Chambers Christopher C Fuerth Benjamin J BJ Viollet Benoit B Mamer Orval A OA Avizonis Daina D DeBerardinis Ralph J RJ Siegel Peter M PM Jones Russell G RG

Cell metabolism 20121227 1

AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed ce ...[more]

PMID: 23274086

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Project description:ObjectiveCircular RNAs (circRNAs), pivotal in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), remain a significant point of investigation for potential therapeutic interventions. Our research was driven by the objective to decipher the roles and underlying mechanisms of hsa_circ_0044569 (circCOL1A1) in governing the malignant phenotypes and the Warburg effect in NPC.MethodsWe systematically collected samples from NPC tissues and normal nasopharyngeal epithelial counterparts. The expression levels of circCOL1A1, microRNA-370-5p (miR-370-5p), and prothymosin alpha (PTMA) were quantitatively determined using quantitative polymerase chain reaction (qPCR) and Western blotting. Transfections in NPC cell lines were conducted using small interfering RNAs (siRNAs) or vectors carrying the pcDNA 3.1 construct for overexpression studies. We interrogated the circCOL1A1/miR-370-5p/PTMA axis's role in cellular functions through a series of assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide for cell viability, colony formation for growth, Transwell assays for migration and invasion, and Western blotting for protein expression profiling. To elucidate the molecular interactions, we employed luciferase reporter assays and RNA immunoprecipitation techniques.ResultsOur investigations revealed that circCOL1A1 was a stable circRNA, highly expressed in both NPC tissues and derived cell lines. A correlation analysis with clinical pathological features demonstrated a significant association between circCOL1A1 expression, lymph node metastasis, and the tumor node metastasis staging system of NPC. Functionally, silencing circCOL1A1 led to substantial suppression of cell proliferation, migration, invasion, and metabolic alterations characteristic of the Warburg effect in NPC cells. At the molecular level, circCOL1A1 appeared to modulate PTMA expression by acting as a competitive endogenous RNA or 'sponge' for miR-370-5p, which in turn promoted the malignant characteristics of NPC cells.ConclusionTo conclude, our findings delineate that circCOL1A1 exerts its oncogenic influence in NPC through the modulation of the miR-370-5p/PTMA signaling axis.

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AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

Publications

AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

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