AMPKα loss promotes KRAS-mediated lung tumorigenesis
- 26 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 28 (9), 2673-2689
- https://doi.org/10.1038/s41418-021-00777-0
Abstract
AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRASG12D increased lung tumour burden and reduced survival in KrasLSLG12D/+/AMPKαfl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.Funding Information
- Cancer Research UK (C5759/A20971)
This publication has 50 references indexed in Scilit:
- The Subread aligner: fast, accurate and scalable read mapping by seed-and-voteNucleic Acids Research, 2013
- AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stressNature, 2012
- AMP-activated protein kinase—an energy sensor that regulates all aspects of cell functionGenes & Development, 2011
- Importance of Molecular Features of Non–Small Cell Lung Cancer for Choice of TreatmentThe American Journal of Pathology, 2011
- Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to MitophagyScience, 2011
- Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor CellsScience, 2009
- Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinaseNature Protocols, 2009
- LKB1 and AMP‐activated protein kinase control of mTOR signalling and growthActa Physiologica, 2009
- AMPK Phosphorylation of Raptor Mediates a Metabolic CheckpointMolecular Cell, 2008
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001