LKB1-AMPK Axis Negatively Regulates Ferroptosis by Inhibiting Fatty Acid Synthesis
29 Pages Posted: 11 Dec 2019 Sneak Peek Status: Review CompleteMore...
Ferroptosis is a form of regulated necrotic cell death characterized by an iron-dependent lipid peroxidation. Although mounting evidence has demonstrated that diverse cellular metabolic processes contribute to ferroptosis, the detail mechanism by which cellular metabolism regulates ferroptosis is largely unknown. Here, we demonstrated that AMP-activated protein kinase (AMPK), a highly conversed master regulator of cellular energy homostasis is a crucial negative regulator of ferroptosis. Activation of AMPK by glucose starvation or a pharmaceutical activator suppresses ferroptotic cell death, and genetic knocking out of AMPK sensitizes cells to ferroptosis. Mechanistically, ferroptosis inducers activate AMPK which in turn phosphorylates acetyl-CoA carboxylase 1 (ACC1), leading to inhibition of fatty acid synthesis, lipid peroxide accumulation and ferroptosis. Importantly, loss of function of tumor suppressor liver kinase B1 (LKB1) sensitizes mouse embryonic fibroblasts (MEFs) and human non-small cell lung carcinoma cell lines to ferroptosis. Collectively, our results demonstrate the vital role of LKB1-AMPK-ACC1-FAS axis in dictating ferroptotic cell death, and suggest that malignant mutations in LKB1-AMPK signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies.
Keywords: Ferroptosis, LKB1, AMPK, Fatty acid synthesis
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