AMPKα loss promotes KRAS-mediated lung tumorigenesis

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.

Automated summary

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.