Abstract 2919: A novel J-series prostamide mediates anandamide-induced endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes
Authors: Eman Soliman, Rukiyah Van Dross, Allison Danell
Journal: Cancer Research (2015)

Abstract Non-melanoma skin cancer (NMSC) and other epithelial tumors overexpress cyclooxygenase-2 (COX-2) differentiating them from normal cells. COX-2 metabolizes arachidonic acid (AA) to H-series prostaglandins (PGs) which are further metabolized by different synthases to E-, F-, and D-series PGs. D-series PGs (PGD2) are then converted to J-series PGs (PGJ2) and these bioactive lipids induce apoptosis by different mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl-ethanolamide (AEA) is a cannabinoid that causes apoptotic cell death in diverse tumor types. The antiproliferative activity of these lipids is mediated by the G-protein coupled receptors, CB1 and CB2. However, recent studies have demonstrated that receptor-independent effects may also account for its activity. Several studies have attributed the receptor-independent cytotoxicity of AEA to COX-2. COX-2 metabolizes AEA to E-, F-, and D-series PG-ethanolamides (PG-EAs). Our previous data showed that AEA is also converted to a novel metabolite, 15 deoxy Δ12,14 prostaglandin J2-ethanolamide (15dPGJ2-EA). J-series PGs that are derived from AA are potent inducers of ER stress-mediated apoptosis. Therefore, the current study examines the role of 15dPGJ2-EA in the activation of the apoptotic ER stress pathway. To determine if AEA is selectively toxic to tumorigenic keratinocytes, tumorigenic (JWF2) and non-tumorigenic (HaCaT) keratinocytes were used. A significant reduction in cell viability was observed in JWF2 but not in HaCaT cells treated with AEA. Interestingly, COX-2 was overexpressed in JWF2 cells suggesting that the selective toxicity of AEA might be attributed to COX-2 overexpression and the production of 15dPGJ2-EA. In tumorigenic JWF2 keratinocytes, AEA induced apoptosis and increased the expression of apoptotic ER stress proteins, C/EBP homologous protein-10 (CHOP10) and caspase-12. In addition, the use of ER stress inhibitors salubrinal and 4-phenylbutyric acid (PBA) inhibited the cytotoxic effect of AEA. To evaluate the role of 15dPGJ2-EA in AEA-induced ER stress-apoptosis, the selective PGD synthase inhibitor, selinium tetrachloride (SeCl4), was used. SeCL4 reduced AEA-mediated synthesis of PGD2, 15dPGJ2, and CHOP10 as well as the initiation of apoptosis. We also confirmed that PGD2-EA was metabolized to 15dPGJ2-EA and increased CHOP expression and caspase-3 cleavage, similar to AEA. Furthermore, we verified that the effect of AEA on ER stress-apoptosis was cannabinoid receptor-independent. These findings implicate 15dPGJ2-EA in AEA-induced ER stress-apoptosis. Since this metabolite is formed in presence of COX-2, AEA may be an ideal topical treatment for NMSC that will be selectively cytotoxic to cancer cells but not detrimental to normal, healthy surrounding cells. Citation Format: Eman Soliman, Rukiyah Van Dross, Allison Danell. A novel J-series prostamide mediates anandamide-induced endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2919. doi:10.1158/1538-7445.AM2015-2919