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Melatonin suppresses cyclosporine A-induced autophagy in rat pituitary GH3 cells.
J Pineal Res. 2010 Jan 28;
Authors: Yoo YM, Jeung EB
Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the induction of chronic nephrotoxicity including endoplasmic reticulum (ER) stress in tubular cells. Recently, it was reported that autophagy is induced by ER stress and serves to alleviate the associated deleterious effects. In the current study, CsA treatment (0-100 mum) decreased cell survival of rat pituitary GH3 cells in a dose-dependent manner. At concentrations ranging from 1.0 to 10 mum, CsA induced a dose-dependent increase in the expression of microtubule-associated protein 1 light chain 3 (LC3)-I and LC3-II. Cells treated with 2.5 mum CsA exhibited cytoplasmic vacuolation, indicating that CsA induces autophagy in rat pituitary GH3 cells. In the presence of 1.0-10 mum CsA, the expression of catalase decreased while that of the ER stress markers, ER luminal binding protein (BiP) and inositol-requiring enzyme 1 alpha (IRE1alpha), increased as compared those levels in untreated cells. These results suggested that CsA-induced autophagy is dependent on ER stress. To determine whether melatonin would protect cells against CsA-induced autophagy, we treated rat pituitary GH3 cells with melatonin in the presence of CsA. Melatonin treatment (100 and 200 mum) suppressed autophagy induced by 2.5 and 5 mum CsA. Furthermore, co-treatment with 100 mum melatonin inhibited LC3-II expression, and increased catalase and phosphorylated p-ERK levels in the presence of 2.5 and 5 mum CsA. BiP and IRE1alpha expression in melatonin-co-treated cells was superior to that in cells treated with 2.5 and 5 mum CsA alone. Thus, melatonin suppresses CsA-mediated autophagy in rat pituitary GH3 cells.
PMID: 20136702 [PubMed - as supplied by publisher]