IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR in hepatocytes, the stroma and cancer cells

Abstract

Interleukin 11 (IL11) stimulates stromal cell activation but also causes hepatocyte metabolic dysfunction. The mechanisms underlying these seemingly unrelated processes are not known. Here we report that IL11-stimulated ERK/P90RSK activity causes the sequential phosphorylation of LKB1 (STK11) at S325 and S428, leading to its inactivation. This leads to a reduction in AMPK activity whilst concomitantly activating mTOR in human fibroblasts, hepatic stellate cells, hepatocytes and cancer cells. In fibroblasts and hepatic stellate cells, IL11-mediated LKB1/AMPK inhibition causes myofibroblast transformation whereas in hepatocytes it inhibits autophagy and fatty acid oxidation and is toxic. Across cell types, the self-amplifying loop of autocrine IL11 activity was inhibited by AMPK activation with metformin, AICAR or 991. In mice on a western diet with fructose, anti-IL11 therapy or hepatocyte-specific deletion of Il11ra1 rescues LKB1/AMPK activity and reduces NASH. In contrast, restoration of IL11 signalling in hepatocytes of mice with global Il11ra1 deletion inactivates LKB1/AMPK and exacerbates NASH. These data show that LKB1, an important tumour suppressor and master kinase, is not constitutively active and identify the IL11/LKB1/AMPK/mTOR axis as a point of signalling convergence for epithelial homeostasis, fibrogenesis, immunometabolism and cancer.

Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer

“…IL11 has been consistently reported to activate STAT3 [ 45 , 46 , 55 ], and upregulates anti-apoptotic pathways driven by BCL2 and Survivin [ 55 ]. Recently, IL11 stimulation has also been found to activate ERK and p90RSK to inhibit LKB1/AMPK and increase mTOR [ 68 ]. LKB1 is an important tumor suppressor for which inactivating mutations are prognostic for poorer outcome and predictive for treatment failure in NSCLC (reviewed in [ 69 , 70 ]).…”