Metabolism of anandamide by COX-2 is necessary for endocannabinoid-induced cell death in tumorigenic keratinocytes
✍ Scribed by Rukiyah T. Van Dross
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 282 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.20515
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✦ Synopsis
Abstract
Nonmelanoma skin cancer is the most prevalent cancer in the United States with ∼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 Δ^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. © 2009 Wiley‐Liss, Inc.