Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt.
Prostaglandins Other Lipid Mediat. 2019 Jun;142:9-23. doi: 10.1016/j.prostaglandins.2019.03.001. Epub 2019 Mar 8.
The combined incidence of melanoma and non-melanoma skin cancer (NMSC) is greater than the incidence of all other malignancies in the US. Previously, we demonstrated that the endocannabinoid, arachidonoyl-ethanolamide (AEA), was a potent inducer of apoptosis in NMSC. The metabolism of AEA to the prostaglandin, PGD-EA, was a prerequisite for AEA cytotoxicity. However, the mechanism of PGD-EA cell death has not been clearly defined. In the present study, we report that PGD-EA causes apoptosis in melanoma and NMSC cells. Mass spectrometry analysis revealed that PGD-EA was dehydrated to three J-series prostaglandins; PGJ-EA, ΔPGJ-EA, and 15deoxy,Δ12,14 PGJ-EA. PGD-EA inhibited the antioxidant activity of glutathione and thioredoxin which then caused oxidative stress. This increase in oxidative stress was accompanied by the activation of endoplasmic reticulum (ER) stress and apoptosis. The effect of PGD-EA was independent of DP1, DP2, and PPARγ receptors suggesting that PGD-EA cytotoxicity was mediated by its metabolic product, 15dPGJ-EA.
黑色素瘤和非黑色素瘤皮肤癌（NMSC）的合并发病率大于美国所有其他恶性肿瘤的发病率。此前，我们证明内源性大麻素，花生四烯酰乙醇胺（AEA）是 NMSC 凋亡的有效诱导剂。AEA 代谢为前列腺素 PGD-EA 是 AEA 细胞毒性的前提。然而，PGD-EA 细胞死亡的机制尚未明确界定。在本研究中，我们报告 PGD-EA 可引起黑色素瘤和 NMSC 细胞凋亡。质谱分析显示，PGD-EA 脱水生成三种 J 系列前列腺素；PGJ-EA、ΔPGJ-EA 和 15dPGJ-EA。PGD-EA 抑制谷胱甘肽和硫氧还蛋白的抗氧化活性，从而导致氧化应激。这种氧化应激的增加伴随着内质网（ER）应激和细胞凋亡的激活。PGD-EA 的作用独立于 DP1、DP2 和 PPARγ 受体，表明 PGD-EA 细胞毒性是由其代谢产物 15dPGJ-EA 介导的。
