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LKB1-AMPK Axis Negatively Regulates Ferroptosis by Inhibiting Fatty Acid Synthesis

29 Pages Posted: 11 Dec 2019 Sneak Peek Status: Review Complete

See all articles by Changzhi Li

Changzhi Li

Harbin Institute of Technology - The HIT Center for Life Sciences

Xuan Dong

Harbin Institute of Technology - The HIT Center for Life Sciences

Wenjing Du

Harbin Institute of Technology - The HIT Center for Life Sciences

Xin Shi

Harbin Institute of Technology - The HIT Center for Life Sciences

Kangjie Chen

Harbin Institute of Technology - The HIT Center for Life Sciences

Wei Zhang

Weill Cornell Medical College - Department of Microbiology and Immunology

Minghui Gao

Harbin Institute of Technology - The HIT Center for Life Sciences

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Abstract

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

Suggested Citation

Li, Changzhi and Dong, Xuan and Du, Wenjing and Shi, Xin and Chen, Kangjie and Zhang, Wei and Gao, Minghui, LKB1-AMPK Axis Negatively Regulates Ferroptosis by Inhibiting Fatty Acid Synthesis (December 6, 2019). CELL-REPORTS-D-19-04815. Available at SSRN: https://ssrn.com/abstract=3499746 or http://dx.doi.org/10.2139/ssrn.3499746
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Changzhi Li

Harbin Institute of Technology - The HIT Center for Life Sciences

China

Xuan Dong

Harbin Institute of Technology - The HIT Center for Life Sciences

China

Wenjing Du

Harbin Institute of Technology - The HIT Center for Life Sciences

China

Xin Shi

Harbin Institute of Technology - The HIT Center for Life Sciences

China

Kangjie Chen

Harbin Institute of Technology - The HIT Center for Life Sciences

China

Wei Zhang

Weill Cornell Medical College - Department of Microbiology and Immunology ( email )

New York, NY
United States

Minghui Gao (Contact Author)

Harbin Institute of Technology - The HIT Center for Life Sciences ( email )

China

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