Journal
CELL DEATH AND DIFFERENTIATION
Volume 28, Issue 9, Pages 2673-2689Publisher
SPRINGERNATURE
DOI: 10.1038/s41418-021-00777-0
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Funding
- CRUK MI core grant [C5759/A20971]
- Lung Cancer Centre [C5759/A20465]
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AMP-activated protein kinase (AMPK) plays a critical role in non-small cell lung cancer, with loss of AMPKα potentially promoting KRAS-mediated lung tumorigenesis. Additionally, AMPKα might regulate LDHB activation through modulation of lncRNA KIMAT1. These findings offer a new axis for therapeutic research.
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 AMPK alpha 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 AMPK alpha in combination with activation of mutant KRAS(G12D) increased lung tumour burden and reduced survival in Kras(LSLG12D/+)/AMPK alpha(fl/fl) mice. In agreement, functional in vitro studies revealed that AMPK alpha silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPK alpha-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPK alpha activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPK alpha loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPK alpha axis that could be exploited for therapeutic purposes.
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