Cytosolic serine hydroxymethyltransferase controls lung adenocarcinoma cells migratory ability by modulating AMP kinase activity

Amani Bouzidi, Maria Chiara Magnifico, Alessandro Paiardini, Alberto Macone, Giovanna Boumis, Giorgio Giardina, Serena Rinaldo, Francesca Romana Liberati, Clotilde Lauro, Cristina Limatola, Chiara Lanzillotta, Antonella Tramutola, Marzia Perluigi, Gianluca Sgarbi, Giancarlo Solaini, Alessandra Baracca, Alessio Paone, Francesca Cutruzzolà

Research output: Contribution to journalArticlepeer-review

Abstract

Nutrient utilization and reshaping of metabolism in cancer cells is a well-known driver of malignant transformation. Less clear is the influence of the local microenvironment on metastasis formation and choice of the final organ to invade. Here we show that the level of the amino acid serine in the cytosol affects the migratory properties of lung adenocarcinoma (LUAD) cells. Inhibition of serine or glycine uptake from the extracellular milieu, as well as knockdown of the cytosolic one-carbon metabolism enzyme serine hydroxymethyltransferase (SHMT1), abolishes migration. Using rescue experiments with a brain extracellular extract, and direct measurements, we demonstrate that cytosolic serine starvation controls cell movement by increasing reactive oxygen species formation and decreasing ATP levels, thereby promoting activation of the AMP sensor kinase (AMPK) by phosphorylation. Activation of AMPK induces remodeling of the cytoskeleton and finally controls cell motility. These results highlight that cytosolic serine metabolism plays a key role in controlling motility, suggesting that cells are able to dynamically exploit the compartmentalization of this metabolism to adapt their metabolic needs to different cell functions (movement vs. proliferation). We propose a model to explain the relevance of serine/glycine metabolism in the preferential colonization of the brain by LUAD cells and suggest that the inhibition of serine/glycine uptake and/or cytosolic SHMT1 might represent a successful strategy to limit the formation of brain metastasis from primary tumors, a major cause of death in these patients.

Original languageEnglish
Pages (from-to)1012
JournalCell death & disease
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 26 2020

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