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Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis.

ABSTRACT: Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF-7 and MDA-MB-231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA-rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA-rich environments. MCF-7 and MDA-MB-231 cells incubated in serum-containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose-dependent manner, with MDA-MB-231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF-7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA-MB-231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate-induced lipotoxicity, with MDA-MB-231 cells being highly sensitive, whereas MCF-7 cells are partially protected. The attenuation of palmitate-induced lipotoxicity in MCF-7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA-MB-231 cells with FAs increased TAG synthesis and reduced palmitate-induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF-7 and MDA-MB-231 cells and how lipid-rich environments modulate these effects.

SUBMITTER: Balaban S

PROVIDER: S-EPMC6120225 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis.

Balaban Seher S Lee Lisa S LS Varney Bianca B Aishah Atqiya A Gao Quanqing Q Shearer Robert F RF Saunders Darren N DN Grewal Thomas T Hoy Andrew J AJ

Molecular oncology 20180829 9

Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF-7 and MDA-MB-231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA-rich, and these FAs are transferred to BrCa cells, we sought to elucidate t ...[more]

PMID: 30099850

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Project description:BackgroundRodent and human β-cells are differentially susceptible to the "lipotoxic" effects of long-chain saturated fatty acids (LC-SFA) but the factors accounting for this are unclear. Here, we have studied the intracellular disposition of the LC-SFA palmitate in human vs rodent β-cells and present data that reveal new insights into the factors regulating β-cell lipotoxicity.MethodsThe subcellular distribution of the LC-SFA palmitate was studied in rodent (INS-1E and INS-1 823/13 cells) and human (EndoC-βH1) β-cells using confocal fluorescence and electron microscopy (EM). Protein expression was assessed by Western blotting and cell viability, by vital dye staining.ResultsExposure of INS-1 cells to palmitate for 24 h led to loss of viability, whereas EndoC-βH1 cells remained viable even after 72 h of treatment with a high concentration (1 mM) of palmitate. Use of the fluorescent palmitate analogue BODIPY FL C16 revealed an early localisation of the LC-SFA to the Golgi apparatus in INS-1 cells and this correlated with distention of intracellular membranes, visualised under the EM. Despite this, the PERK-dependent ER stress pathway was not activated under these conditions. By contrast, BODIPY FL C16 did not accumulate in the Golgi apparatus in EndoC-βH1 cells but, rather, co-localised with the lipid droplet-associated protein, PLIN2, suggesting preferential routing into lipid droplets. When INS-1 cells were treated with a combination of palmitate plus oleate, the toxic effects of palmitate were attenuated and BODIPY FL C16 localised primarily with PLIN2 but not with a Golgi marker.ConclusionIn rodent β-cells, palmitate accumulates in the Golgi apparatus at early time points whereas, in EndoC- βH1 cells, it is routed preferentially into lipid droplets. This may account for the differential sensitivity of rodent vs human β-cells to "lipotoxicity" since manoeuvres leading to the incorporation of palmitate into lipid droplets is associated with the maintenance of cell viability in both cell types.

Dataset Information

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis.

Publications

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis.

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