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

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 wellunderstood. 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 Methionine (Met) metabolism is an integral aspect in cellular function and is particularly important in cancer. Cancer cells that cannot proliferate in growth medium when Met is replaced with its metabolic precursor, homocysteine (Hcy), have been character-

Over-methylation of Histone H3 Lysines Is a Common Molecular Change Among the Three Major Types of Soft-tissue Sarcoma in Patient-derived Xenograft (PDX) Mouse Models

“…Future studies will also use other methods to investigate epigenetic modifications of histones in cancer, such as ChIP (23). The overmethylation of H3K4me3 and H3K9me3 found in the 3 major types of sarcoma in the present study may be related to methionine addiction, a fundamental hallmark of cancer (24)(25)(26)(27)(28), termed the Hoffman effect (29)(30)(31). The over-methylation of these histone marks required excess methionine in the form of S-adenosylmethionine and may, at least in part, account for the excess methionine required by cancer cells and is a basis why methionine restriction with recombinant methioninase has been an effective therapy for sarcoma in all major types of sarcoma PDOX models (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”

Efficacy of Oral Recombinant Methioninase and Eribulin on a PDOX Model of Triple-negative Breast Cancer (TNBC) Liver Metastasis

“…The present study showed o-rMETase significantly inhibited growth of livermetastasis TNBC. o-rMETase is of particular importance as it targets the methionine addiction of cancer, which is a fundamental and general hallmark of cancer discovered by us (12)(13)(14)(15)(16)(17)(18)(19)(20) and which is termed the Hoffman effect (21)(22)(23). Future clinical studies will combine low-dose chemotherapy with o-rMETase for TNBC to overcome the recalcitrance of this disease.…”

Advances in Analyzing the Breast Cancer Lipidome and Its Relevance to Disease Progression and Treatment

“…For example, methionine (Met) is an essential amino acid required for cancer cells to grow under in vitro conditions and is also important in lipid biosynthesis due to the requirement for S-adenyl-methionine [77]. Borrego et al assessed the impact of Met stress (deprivation) on the cellular lipid composition of TNBC MDA-MB-468 cells and a Met stress insensitive derivative, MDA-MB-468res-R8, under control and Met-stress conditions [78]. There was a rapid and extensive decrease in lipid abundance, except for unsaturated TGs, in Met-dependent MDA-MB-468 cells that was not observed in Met-res cells, and there was an associated increase in cytoplasmic lipid droplets reflecting an overall increase in neutral storage lipids.…”

“…The second obstacle is the types of breast cancer models used in previous published work. The majority of lipidomic studies discussed in this review used either breast cancer cell lines [69,71,73,76,78,81] or primary tumor samples [83][84][85][86]. As highlighted in Table 1, there is a clear disparity between lipid analytes detected in 2D cell line monoculture versus patient tumor samples, with only several key overlapping lipid species.…”