PXD040655-1

PXD040655 is an original dataset announced via ProteomeXchange.

Title	Methionine stress induces ferroptosis in methionine dependent cancer cells
Description	Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We found that replacing methionine with homocysteine generally induced hypomethylation in gene promoters. We isolated nuclear proteins and submitted it for tandem mass tag (TMT) proteomics. This analysis revealed that several proteins involved in the mitochondrial integrated stress response (ISR) were upregulated in response to the replacement of methionine to homocysteine in both cell lines, but to a much greater degree in the methionine dependent cell line. Consistent with the ISR signature, a proteomic analysis of a subcellular fraction enriched for mitochondrial content revealed a strong enrichment for proteins involved in oxidative phosphorylation. Analysis of cellular bioenergetics confirmed that homocysteine induces a decrease in ATP production from oxidative phosphorylation and glycolysis, but to a similar extent in methionine dependent and methionine independent cells. The mitochondrial integrated stress response shared a signature with ferroptosis. Methionine dependent cells displayed a strong ferroptotic signature, which was decreased by half in methionine independent cells. Consistent with ferroptosis, malonaldehyde was increased in methionine independent cells grown in homocysteine, and viability could be rescued with the inhibitor ferrostatin. Therefore, we propose that methionine stress induces ferroptotic cell death in methionine dependent cancer cells.
HostingRepository	MassIVE
AnnounceDate	2023-09-14
AnnouncementXML	Submission_2023-09-14_05:38:38.809.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Stephanie Byrum
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Oxidation; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-07 05:40:50	ID requested
⏵ 1	2023-09-14 05:38:39	announced

no publication

submitter keyword: methionine, ferroptosis, melanoma

Isabelle Racine Miousse
contact affiliation	University of Arkansas for Medical Sciences
contact email	IRacinemiousse@uams.edu
lab head
Stephanie Byrum
contact affiliation	University of Arkansas for Medical Sciences
contact email	sbyrum@uams.edu
dataset submitter

MassIVE dataset URI

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