Metabolism of anandamide by COX-2 is necessary for endocannabinoid-induced cell death in tumorigenic keratinocytes.
Nonmelanoma skin cancer is the most prevalent cancer in the United States with approximately 1.25 million new cases diagnosed each year. Cyclooxygenase-2 (COX-2) expression is commonly elevated in these and other epithelial tumors. Cyclooxygenases metabolize arachidonic acid to prostaglandins, which promote growth and survival of tumor cells. COX-2 also metabolizes endocannabinoids forming prostaglandin-ethanolamides (PG-EA); however, the role of these lipid molecules in tumor cell survival is unclear. The goal of this research is to determine if the metabolic products of COX-2 contribute to endocannabinoid-induced cell death. Anandamide [also known as arachidonyl ethanolamide (AEA)] induced cell death in the COX-2 overexpressing squamous carcinoma cell line JWF2. In contrast, AEA did not initiate cell death in HaCaT keratinocytes, which express low basal levels of COX-2. Resistance to AEA-mediated cell death in HaCaT cells was reversed by overexpressing COX-2 in these cells. Next, ELISA assays were carried out to identify prostaglandins involved in AEA-mediated cell death. D-type prostaglandins were predominantly formed in AEA-exposed JWF2 cells although significant increases in E- and F-type prostaglandins were also seen. Cells were then treated with various prostaglandins or PG-EA to determine the contribution of each to AEA-induced cell death. PGD(2) and PGD(2)-EA were found to be cytotoxic to JWF2 keratinocytes and the PGD(2) dehydration products, PGJ(2) and 15-deoxy Delta(12,14) PGJ(2), were also potent inducers of cell death. These results suggest that AEA selectively induces cell death in tumorigenic keratinocytes due to COX-2 overexpression and the resulting metabolism of AEA to cytotoxic prostaglandins.
Van Dross
Rukiyah T
RT
Department of Pharmacology and Toxicology, East Carolina University, Brody School of Medicine, Greenville, North Carolina 28590, USA.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000494:pharmacology*; D063388:Endocannabinoids; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D051546:Cyclooxygenase 2; C078814:anandamide