title: Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase-2 and novel J-series prostamides.
abstract: Non-melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase-2 (COX-2), differentiating them from normal cells. COX-2 metabolizes arachidonic acid to prostaglandins including, the J-series prostaglandins, which induce apoptosis by mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl-ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types. Previous studies from our group demonstrated that AEA was metabolized by COX-2 to J-series prostaglandins. Thus, the current study examines the role of COX-2, J-series prostaglandins, and ER stress in AEA-induced apoptosis. In tumorigenic keratinocytes that overexpress COX-2, AEA activated the PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE1), and activating transcription factor-6 (ATF6) ER stress pathways and the ER stress apoptosis-associated proteins, C/EBP homologous protein-10 (CHOP10), caspase-12, and caspase-3. Using an ER stress inhibitor, it was determined that ER stress was required for AEA-induced apoptosis. To evaluate the role of COX-2 in ER stress-apoptosis, HaCaT keratinocytes with low endogenous COX-2 expression were transfected with COX-2 cDNA or an empty vector and AEA-induced ER stress-apoptosis occurred only in the presence of COX-2. Moreover, LC-MS analysis showed that the novel prostaglandins, 15-deoxyΔ(12,14) PGJ2 -EA and Δ(12) PGJ2 /PGJ2-EA, were synthesized from AEA. These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX-2 due to the metabolism of AEA by COX-2 to J-series prostaglandin-ethanolamides (prostamides). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2.
authors.affiliation: Brody School of Medicine, Pharmacology and Toxicology, East Carolina University, Greenville, NC.
authors.forename: Eman
authors.initials: E
authors.lastname: Soliman
authors.affiliation: Department of Chemistry, East Carolina University, Greenville, NC.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Henderson
authors.affiliation: Department of Chemistry, East Carolina University, Greenville, NC.
authors.forename: Allison S
authors.initials: AS
authors.lastname: Danell
authors.affiliation: Brody School of Medicine, Pharmacology and Toxicology, East Carolina University, Greenville, NC.
authors.forename: Rukiyah
authors.initials: R
authors.lastname: Van Dross
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D063388:Endocannabinoids / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D011453:Prostaglandins; D051546:Cyclooxygenase 2; C078814:anandamide
keywords: AEA; COX-2; J-series prostaglandins; cannabinoids; selective toxicity