Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion

Iain Brown, Jisun Lee, Alan A. Sneddon, Maria G. Cascio, Roger G. Pertwee, Klaus W.J. Wahle, Dino Rotondo, Steven D. Heys

Research output: Contribution to journalArticle

Abstract

The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin b3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.
Original languageEnglish
Article number102024
JournalProstaglandins, Leukotrienes and Essential Fatty Acids
Early online date16 Oct 2019
DOIs
Publication statusE-pub ahead of print - 16 Oct 2019

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Endocannabinoids
Ethanolamine
Cell growth
Breast Neoplasms
Derivatives
Growth
Cell Movement
Cells
Cannabinoid Receptor CB1
Phosphorylation
Proteins
MCF-7 Cells
Therapeutic Uses
p38 Mitogen-Activated Protein Kinases
Matrix Metalloproteinases
Unsaturated Fatty Acids
Integrins
Vascular Endothelial Growth Factor A
Cell Survival
Breast

Keywords

  • Omega (N)-3 Fatty Acids
  • N-acylethanolamides (NAEs)
  • Endocannabinoids
  • Breast Cancer
  • Cannabinoid Receptors (CBRs)
  • MAP kinase signalling
  • cell proliferation
  • Cell proliferation
  • Omega (N)-3 fatty acids
  • Cannabinoid receptors (CBRs)
  • Breast cancer

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology

Cite this

@article{95185b85d3cb43c4aff62ae2f2961a9a,
title = "Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion",
abstract = "The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin b3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.",
keywords = "Omega (N)-3 Fatty Acids, N-acylethanolamides (NAEs), Endocannabinoids, Breast Cancer, Cannabinoid Receptors (CBRs), MAP kinase signalling, cell proliferation, Cell proliferation, Omega (N)-3 fatty acids, Cannabinoid receptors (CBRs), Breast cancer",
author = "Iain Brown and Jisun Lee and Sneddon, {Alan A.} and Cascio, {Maria G.} and Pertwee, {Roger G.} and Wahle, {Klaus W.J.} and Dino Rotondo and Heys, {Steven D.}",
note = "Acknowledgements We would like to acknowledge NHS Grampian Endowment funds and TENOVUS Scotland for funding. JL was funded by a scholarship from Fraserburgh Moonlight Prowl and AAS was funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). We also thank Dr Raphael Mechoulam, University of Jerusalem, for the gift of the endocannabinoids.",
year = "2019",
month = "10",
day = "16",
doi = "10.1016/j.plefa.2019.102024",
language = "English",
journal = "Prostaglandins, Leukotrienes and Essential Fatty Acids",
issn = "0952-3278",
publisher = "Churchill Livingstone",

}

TY - JOUR

T1 - Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion

AU - Brown, Iain

AU - Lee, Jisun

AU - Sneddon, Alan A.

AU - Cascio, Maria G.

AU - Pertwee, Roger G.

AU - Wahle, Klaus W.J.

AU - Rotondo, Dino

AU - Heys, Steven D.

N1 - Acknowledgements We would like to acknowledge NHS Grampian Endowment funds and TENOVUS Scotland for funding. JL was funded by a scholarship from Fraserburgh Moonlight Prowl and AAS was funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). We also thank Dr Raphael Mechoulam, University of Jerusalem, for the gift of the endocannabinoids.

PY - 2019/10/16

Y1 - 2019/10/16

N2 - The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin b3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.

AB - The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin b3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.

KW - Omega (N)-3 Fatty Acids

KW - N-acylethanolamides (NAEs)

KW - Endocannabinoids

KW - Breast Cancer

KW - Cannabinoid Receptors (CBRs)

KW - MAP kinase signalling

KW - cell proliferation

KW - Cell proliferation

KW - Omega (N)-3 fatty acids

KW - Cannabinoid receptors (CBRs)

KW - Breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85074507575&partnerID=8YFLogxK

U2 - 10.1016/j.plefa.2019.102024

DO - 10.1016/j.plefa.2019.102024

M3 - Article

C2 - 31679810

JO - Prostaglandins, Leukotrienes and Essential Fatty Acids

JF - Prostaglandins, Leukotrienes and Essential Fatty Acids

SN - 0952-3278

M1 - 102024

ER -