Research Article
Lipid remodeling in response to methionine stress in MDA-MBA-468 triple-negative breast cancer cells

https://doi.org/10.1016/j.jlr.2021.100056Get rights and content
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Abstract

Methionine (Met) is an essential amino acid and critical precursor to the cellular methyl donor S-adenosylmethionine. Unlike nontransformed cells, cancer cells have a unique metabolic requirement for Met and are unable to proliferate in growth media where Met is replaced with its metabolic precursor, homocysteine. This metabolic vulnerability is common among cancer cells regardless of tissue origin and is known as “methionine dependence”, “methionine stress sensitivity”, or the Hoffman effect. The response of lipids to Met stress, however, is not well-understood. Using mass spectroscopy, label-free vibrational microscopy, and next-generation sequencing, we characterize the response of lipids to Met stress in the triple-negative breast cancer cell line MDA-MB-468 and its Met stress insensitive derivative, MDA-MB-468res-R8. Lipidome analysis identified an immediate, global decrease in lipid abundances with the exception of triglycerides and an increase in lipid droplets in response to Met stress specifically in MDA-MB-468 cells. Furthermore, specific gene expression changes were observed as a secondary response to Met stress in MDA-MB-468, resulting in a downregulation of fatty acid metabolic genes and an upregulation of genes in the unfolded protein response pathway. We conclude that the extensive changes in lipid abundance during Met stress is a direct consequence of the modified metabolic profile previously described in Met stress–sensitive cells. The changes in lipid abundance likely results in changes in membrane composition inducing the unfolded protein response we observe.

Supplementary key words

cancer metabolism
homocysteine
methionine
methionine stress
lipid metabolism
lipid droplets
phospholipids
fatty acid metabolism
triglycerides

Abbreviations

ASNS
asparagine synthetase
CARS
coherent anti-Stokes Raman scattering
CHOP
C/EBP Homologous Protein
DAG
diacyglycerol
Hcy
homocysteine
MB468
shortened for MDA-MB-468 triple negative breast cancer cells
MB468res-R8
Resistant cell line derived from MB468, also referred to as “R8”
Met
methionine
MS
methionine synthase
PC
phosphatidylcholine
PE
phosphatidylethanolamine
SAH
S-adenosylhomocysteine
SAM
S-adenosylmethionine
SRS
stimulated Raman scattering
UPR
unfolded protein response

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