Prolyl isomerase Pin1 regulates cadmium-induced autophagy via ubiquitin-mediated post-translational stabilization of phospho-Ser GSK3?? in human hepatocellular carcinoma cells.

Accumulating evidence suggests that prolyl-isomerase (Pin1) is an important regulator of apoptosis. In the present study, Pin1 was shown to negatively regulate the stabilization of glycogen synthase kinase (GSK) 3?? serine phosphorylation by inhibiting ubiquitin (Ub)-proteasome degradation, and to induce autophagy following cadmium (Cd) exposure. Cd-induced autophagy in human hepatoma ...
(HepG2) cells has been demonstrated by green fluorescent protein (GFP)-LC3B plasmid DNA transfection, and LC3-II conversion by autophagy inhibitors. Atg5 silencing inhibited Cd-induced apoptosis, indicating that autophagy is involved in cell death. Exposing HepG2 cells to Cd (?6 ?M) initially increased p-Ser GSK3??, but then resulted in a gradual decrease, which correlated with polyubiquitinated protein levels, which is indicative of protein degradation. However, high Cd concentrations lead to p-Ser GSK3?? and polyubiquitinated protein accumulation, indicating proteasome impairment. Cd-induced p-Ser GSK3?? was enhanced by proteasome inhibition (MG132) and ubiquitin deficiency (cyclohexamide), but no ubiquitination of p-Ser GSK3?? or GSK3?? was detected. Cd exposure resulted in p-Ser GSK3?? redistribution from the nucleus into the cytosol, and this along with autophagy, was inhibited by leptomycin B. Cd concentrations <6 ?M did not alter Pin1; however, Cd?6 ?M decreased Pin1. Pin1 overexpression decreased Cd-induced p-Ser GSK3??, autophagy, and polyubiquitinated protein levels, while its inhibition reversed the effects. Silencing and overexpression of GSK3?? had no effect on Cd-induced Pin1 levels. Immunoprecipitation studies showed that Pin1 and p-Ser GSK3?? interact. Collectively, Pin1 protects cells by inhibiting p-Ser GSK3??, and Pin1 decrease upregulates p-Ser GSK3??, through the inhibition of Ub-mediated proteasome degradation, and stimulates cell death via autophagy.
Mesh Terms:
Apoptosis, Autophagy, Cadmium, Cell Line, Tumor, Enzyme Stability, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, NIMA-Interacting Peptidylprolyl Isomerase, Peptidylprolyl Isomerase, Phosphorylation, Protein Processing, Post-Translational, Serine, Ubiquitin
Biochem. Pharmacol.
Date: Dec. 01, 2015
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