Sterculic acid inhibits fenretinide-induced apoptosis in human retinal pigment epithelial cells

Abstract

AbstractThe ratio of saturated to monounsaturated fatty acids, thought to play a critical role in many cellular functions, is regulated by stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. Previously, we observed a decrease in both SCD protein and enzymatic activity in apoptosis induced by fenretinide, a synthetic analog of retinoic acid, in the human retinal pigment epithelial (RPE) cell line ARPE-19. Here, we investigated the effect of sterculic acid, a cyclopropenoic fatty acid inhibitor of SCD, on fenretinide-induced apoptosis, given the role of SCD in cell proliferation and apoptosis. We show that sterculic acid abrogates the effects of fenretinide-induced apoptosis shown by changes in cell morphology, viability, and caspase-3 activation. Analysis of endoplasmic reticulum (ER)-associated proteins shows that sterculic acid reduced the fenretinide upregulated expression of heme oxygenase-1, ATF3 and GADD153 that are in response to reactive oxygen species (ROS) generation. Furthermore, sterculic acid elicits a similar degree of inhibition of fenretinide-induced ROS generation by xanthine oxidase as does allopurinol, and also reduces SOD2 expression. Dihydroceramide accumulation, compared to ceramide, and ROS generation indicate that a ceramide-independent pathway mediates apoptosis. Fenretinide-induced activation of NF-kBp50 and NF-kBp65 illuminates the signaling cascade downstream of ROS generation. Its inhibition by sterculic acid further indicates the latter’s antioxidant/anti-inflammatory effect. Taken together, our results suggest that sterculic acid can mitigate fenretinide-induced apoptosis and may serve as a potential antioxidant and therapeutic agent. These effects may be independent of its effects on SCD activity