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Docosahexanoic Acid Improves Chemotherapy Efficacy by Inducing CD95 Translocation to Lipid Rafts in ER− Breast Cancer Cells

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Lipids

Abstract

Docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) have been shown to possess anti-carcinogenic properties in mammary cancers, both in vitro and in vivo. The objective of this study was to investigate the effect of treating three different breast cancer cell lines with DHA or EPA on cellular growth, chemotherapy efficacy, and CD95 expression and localization in the cell. MDA-MB-231, MCF-7 and SKBr-3 cells were incubated with EPA or DHA with or without chemotherapy agents [doxorubicin (dox), Herceptin]. Cell growth was assessed by WST-1 assay and CD95 expression was investigated using flow cytometry, Western blotting and confocal microscopy. DHA and EPA inhibited the growth of all three breast cancer cell lines in a dose-dependent fashion (P < 0.05). DHA, and to a lesser extent EPA, induced the movement and raft clustering of CD95 in the cell membrane (via confocal microscopy) and the surface expression (via flow cytometry) in MDA-MB-231 cells. Neither fatty acid altered the growth/metabolic activity of the non-transformed MCF-12A breast cell line. Pre-treatment with DHA, but not EPA, improved the efficacy of dox in estrogen receptor negative MDA-MB-231 cells (P < 0.05), but not in the other two cell lines. Pre-treating cells with DHA increased CD95 surface expression (threefold) and the plasma membrane raft content of CD95 (2fold) and FADD (>4-fold) after dox treatment, compared to dox treatment alone (P < 0.05). This study demonstrated that pre-treatment of estrogen receptor negative MDA-MB-231 cells with DHA increased the anti-cancer effects of dox and presents evidence to suggest that this may be mediated in part by CD95-induced apoptosis.

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Abbreviations

DAPI:

4′,6′-Diamidino-2-phenylindole

DHA:

Docosahexanoic acid

DISC:

Death-inducing signaling complex

EPA:

Eicosapentanoic acid

ER:

Estrogen receptor

FADD:

Fas-associated death domain-containing protein

LNA:

Linoleic acid

OLA:

Oleic acid

PUFA:

Polyunsaturated fatty acid(s)

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Acknowledgments

Study funding provided by the Canadian Institutes of Health Research (CIHR). J. Ewaschuk was a recipient of a CIHR post-doctoral fellowship.

Conflict of interest

The authors have no conflict of interest to report.

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Authors and Affiliations

  1. Department of Agricultural, Food and Nutritional Sciences, 4-126A Li Ka Shing Health Research Innovation Centre, University of Alberta, Edmonton, AB, T6G 2E1, Canada

    Julia B. Ewaschuk, Marnie Newell & Catherine J. Field

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  1. Julia B. Ewaschuk
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  2. Marnie Newell
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  3. Catherine J. Field
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Correspondence to Catherine J. Field.

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Ewaschuk, J.B., Newell, M. & Field, C.J. Docosahexanoic Acid Improves Chemotherapy Efficacy by Inducing CD95 Translocation to Lipid Rafts in ER− Breast Cancer Cells. Lipids 47, 1019–1030 (2012). https://doi.org/10.1007/s11745-012-3717-7

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  • DOI: https://doi.org/10.1007/s11745-012-3717-7

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