Autophagy regulation and redox perturbation by transcrocetin suppress the growth of endometriosis

Abstract

Until non-hormonal therapeutic targets for endometriosis are suggested, we focused on mitochondrial function and autophagy regulation in the disease. Transcrocetin is a carotenoid and retinoic acid with high antioxidant potency and antiproliferative effects in several diseases. In this study, we demonstrated the therapeutic mechanisms of transcrocetin in endometriosis using the End1/E6E7 and VK2/E6E7 cell lines. Transcrocetin suppressed the viability and proliferation of these cell lines and did not affect the proliferation of normal uterine stromal cells. p21 Waf1/Cip1 as a cell cycle regulator and target of p53, were increased by transcrocetin and caused the G1 arrest via inhibition of cyclin-dependent kinase activity, which might further cause cell death. Furthermore, we confirmed endoplasmic reticulum stress and calcium ion dysregulation in the cytosol and mitochondrial matrix, disrupting the mitochondrial membrane potential. Mitochondrial bioenergetics were suppressed by transcrocetin, and oxidative phosphorylation-related gene expression was downregulated. Moreover, the proliferation of End1/E6E7 and VK2/E6E7 cells was regulated by transcrocetin-induced oxidative stress. Finally, we verified the impairment of autophagic flux following pre-treatment with chloroquine. Therefore, transcrocetin may be a potent therapeutic alternative for endometriosis.