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Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade.

Abstract

The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a cyclooxygenase-2 (COX-2)-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which over-express COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ(12,14) PGJ(2) and PGJ(2)) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or transient receptor potential cation channel, subfamily V, member 1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that over-express COX-2.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology and Toxicology, East Carolina University, Brody School of Medicine, Greenville, North Carolina 27834, USA.

    ,

    Source

    Molecular carcinogenesis 51:2 2012 Feb pg 139-49

    MeSH

    Amidohydrolases
    Animals
    Apoptosis
    Arachidonic Acids
    Blotting, Western
    Cell Line, Tumor
    Endocannabinoids
    In Situ Nick-End Labeling
    Mice
    Polyunsaturated Alkamides
    Prostaglandins
    Receptors, Cannabinoid

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21432910

    Citation

    Kuc, Christian, et al. "Arachidonoyl Ethanolamide (AEA)-induced Apoptosis Is Mediated By J-series Prostaglandins and Is Enhanced By Fatty Acid Amide Hydrolase (FAAH) Blockade." Molecular Carcinogenesis, vol. 51, no. 2, 2012, pp. 139-49.
    Kuc C, Jenkins A, Van Dross RT. Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade. Mol Carcinog. 2012;51(2):139-49.
    Kuc, C., Jenkins, A., & Van Dross, R. T. (2012). Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade. Molecular Carcinogenesis, 51(2), pp. 139-49. doi:10.1002/mc.20770.
    Kuc C, Jenkins A, Van Dross RT. Arachidonoyl Ethanolamide (AEA)-induced Apoptosis Is Mediated By J-series Prostaglandins and Is Enhanced By Fatty Acid Amide Hydrolase (FAAH) Blockade. Mol Carcinog. 2012;51(2):139-49. PubMed PMID: 21432910.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade. AU - Kuc,Christian, AU - Jenkins,Audrey, AU - Van Dross,Rukiyah T, Y1 - 2011/03/22/ PY - 2010/07/27/received PY - 2011/02/01/revised PY - 2011/02/18/accepted PY - 2011/3/25/entrez PY - 2011/3/25/pubmed PY - 2012/2/14/medline SP - 139 EP - 49 JF - Molecular carcinogenesis JO - Mol. Carcinog. VL - 51 IS - 2 N2 - The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a cyclooxygenase-2 (COX-2)-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which over-express COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ(12,14) PGJ(2) and PGJ(2)) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or transient receptor potential cation channel, subfamily V, member 1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that over-express COX-2. SN - 1098-2744 UR - https://www.unboundmedicine.com/medline/citation/21432910/abstract/Arachidonoyl_ethanolamide__AEA__induced_apoptosis_is_mediated_by_J_series_prostaglandins_and_is_enhanced_by_fatty_acid_amide_hydrolase__FAAH__blockade_ L2 - https://doi.org/10.1002/mc.20770 DB - PRIME DP - Unbound Medicine ER -