Steviol stimulates proteasomal-mediated β-catenin degradation in Madin-Darby canine kidney cells
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Abstract
Cystogenesis in autosomal dominant polycystic kidney disease (ADPKD) involved cAMP-stimulated epithelial cell proliferation to form the cyst-ling cell. Our previous study showed that steviol at a concentration of 100 µM reversibly inhibited MDCK cyst growth by 38.3% without any effect on cytotoxicity. In addition, steviol suppressed cell proliferation through the inhibition of mTOR/S6K signaling in PKD mouse model. However, the mechanisms of steviol on cell proliferation pathway have not been evaluated in MDCK cells. This study was aimed to investigate detailed mechanisms of steviol on cell proliferation to slow MDCK cyst growth. Method: Western blot analysis was performed. Results: Steviol at a concentration of 100 µM reduced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) by 45-50% at 6 and 24 h of incubation in MDCK cell monolayers. Steviol also inhibited β-catenin expression by 34-41% at 6 and 24 h of incubation. Interestingly, steviol also suppressed phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), an activated protein for inducing β-catenin accumulation in cytosol. In addition, treatment with 50 µM MG-132, a proteasome inhibitor, significantly abolished the effect of steviol on β-catenin expression. Conclusion: These findings suggested that steviol retarded MDCK cyst enlargement, in part, by reducing cell proliferation through the promotion of proteasome induced β-catenin degradation and ERK1/2 signaling pathways. Steviol represented a promising natural plant-based drug candidate for polycystic kidney disease.
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