Omega-3 PUFA ethanolamides DHEA and EPEA induce autophagy through PPARγ activation in MCF-7 breast cancer cells.
The omega-3 long chain polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), elicit anti-proliferative effects in cancer cell lines and in animal models. Dietary DHA and EPA can be converted to their ethanolamide derivatives, docosahexaenoyl ethanolamine (DHEA), and eicosapentaenoyl ethanolamine (EPEA), respectively; however, few studies are reported on ... their anti-cancer activities. Here, we demonstrated that DHEA and EPEA were able to reduce cell viability in MCF-7 breast cancer cells whereas they did not elicit any effects in MCF-10A non-tumorigenic breast epithelial cells. Since DHA and EPA are ligands of peroxisome proliferator-activated receptor gamma (PPARγ), we sought to determine whether PPARγ may also mediate DHEA and EPEA actions. In MCF-7 cells, both compounds enhanced PPARγ expression, stimulated a PPAR response element-dependent transcription as confirmed by the increased expression of its target gene PTEN, resulting in the inhibition of AKT-mTOR pathways. Besides, DHEA and EPEA treatment induced phosphorylation of Bcl-2 promoting its dissociation from beclin-1 which resulted in autophagy induction. We also observed an increase of beclin-1 and microtubule-associated protein 1 light chain 3 expression along with an enhanced autophagosomes formation as revealed by mono-dansyl-cadaverine staining. Finally, we demonstrated the involvement of PPARγ in DHEA- and EPEA-induced autophagy by using siRNA technology and a selective inhibitor. In summary, our data show that the two omega-3 ethanolamides exert anti-proliferative effects by inducing autophagy in breast cancer cells highlighting their potential use as breast cancer preventive and/or therapeutic agents.
Mesh Terms:
Antineoplastic Agents, Apoptosis Regulatory Proteins, Autophagy, Breast Neoplasms, Cell Proliferation, Cell Survival, Docosahexaenoic Acids, Dose-Response Relationship, Drug, Eicosapentaenoic Acid, Ethanolamine, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Membrane Proteins, Microtubule-Associated Proteins, PPAR gamma, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Time Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Up-Regulation
Antineoplastic Agents, Apoptosis Regulatory Proteins, Autophagy, Breast Neoplasms, Cell Proliferation, Cell Survival, Docosahexaenoic Acids, Dose-Response Relationship, Drug, Eicosapentaenoic Acid, Ethanolamine, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Membrane Proteins, Microtubule-Associated Proteins, PPAR gamma, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Time Factors, Transcription, Genetic, Transcriptional Activation, Transfection, Up-Regulation
J. Cell. Physiol.
Date: Jun. 01, 2013
PubMed ID: 23168911
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