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

Methionine is an essential amino acid and critical precursor to the cellular methyl donor S-adenosylmethionine. Unlike non-transformed cells, cancer cells have a unique metabolic requirement for methionine and are unable to proliferate in growth media where methionine 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 Hoffman effect. Here, we characterize the response of lipids to methionine stress in the triple negative breast cancer cell line MDA-MB-468 and its methionine 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 methionine stress specifically in MDA-MB468 cells. Furthermore, specific gene expression changes were observed as a secondary response to methionine stress in MDA-MB-468, resulting in a down-regulation of fatty acid metabolic genes and up-regulation of genes in the unfolded protein response pathway. We conclude that the extensive changes in lipid abundance during methionine stress is a direct consequence of the modified metabolic profile previously described in methionine stress sensitive cells. The changes in lipid abundance likely results in changes in membrane composition inducing the unfolded protein response we observe. RNA profiles of the triple-negative, methionine-sensitive breast cancer line MDA-MB-468 and its methionine-insensitive derivitive cell line MDA-MB-468res-R8 during methionine stress.