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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 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.

SUBMITTER: Borrego SL

PROVIDER: S-EPMC8042402 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The lack of hormone receptors in triple negative breast cancer (TNBC) is associated with the inefficacy of anti-estrogen chemotherapies, leaving fewer options for patient treatment and higher mortality rates. Additionally, as with numerous types of inflammatory breast cancer, infiltration of tumor associated macrophages and other leukocyte sub-populations within the tumor inevitably lead to aggressive, chemo-resistant, metastatic and invasive types of cancer which escape immune surveillance. These processes are orchestrated by the release of potent cytokines, including TNF?, IL-6 and CCL2 from the stroma, tumor and immune cells within the tumor microenvironment. The present study evaluated apigenin modulating effects on the pro-inflammatory activating action of TNF? in TNBC MDA-MB-468 cells, derived from an African American woman. Initially, cell viability was determined to establish an optimal sub-lethal dose of TNF? and apigenin in MDA-MB-468 cells. Subsequently, various treatments effects were evaluated using whole transcriptomic analysis of mRNA and long intergenic non-coding RNA with Affymetrix HuGene-2.1-st human microarrays. Gene level differential expression analysis was conducted on 48,226 genes where TNF? caused significant upregulation of 53 transcripts and downregulation of 11 transcripts. The largest upward differential shift was for CCL2 [+61.86 fold change (FC); false discovery rate (FDR), P<0.0001]; which was down regulated by apigenin (to +10.71 FC vs. Control; FDR P-value <0.001), equivalent to an 83% reduction. Several TNF? deferentially upregulated transcripts were reduced by apigenin, including CXCL10, C3, PGLYRP4, IL22RA2, KMO, IL7R, ROS1, CFB, IKBKe, SLITRK6 (a checkpoint target) and MMP13. Confirmation of CCL2 experimentally induced transcript alterations was corroborated at the protein level by ELISA assays. The high level of CCL2 transcript in the cell line was comparable to that in our previous studies in MDA-MB-231 cells. The differential effects of TNF? were corroborated by ELISA, where the data revealed a >10-fold higher releasing rate of CCL2 in MDA-MB-468 cells compared with in MDA-MB-231 cells, both of which were attenuated by apigenin. The data obtained in the present study demonstrated a high level of CCL2 in MDA-MB-468 cells and a possible therapeutic role for apigenin in downregulating TNF?-mediated processes in these TNBC cells.

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

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