Prostaglandin D-ethanolamide induces skin cancer apoptosis by suppressing the activity of cellular antioxidants.

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.