title: Autophagy regulated by prolyl isomerase Pin1 and phospho-Ser-GSK3αβ involved in protection of oral squamous cell carcinoma against cadmium toxicity.
abstract: Prolyl isomerase Pin1 plays an important role in cell proliferation and is overexpressed in many human tumors. However, its role in autophagy induction remains undefined. Here we show that Pin1 regulates cell survival via autophagy in cadmium (Cd)-exposed oral squamous cell carcinoma (OSCC). OSCC exposure to Cd induced autophagy, as demonstrated by the formation of green fluorescent punctae in transfected cells expressing GFP-conjugated microtubule-associated protein light chain 3 (LC3) and by LC3 flux in the presence of autophagy inhibitors. Suppression of Atg5 enhanced Cd-induced apoptosis, indicating that autophagy is involved in cell protection. In dose-response experiments, cleavage of procaspase-3, PARP-1, and LC3-II was induced by Cd with an IC50 of 45 μM. Expression of Pin1 was decreased at or above the Cd IC50 value and was inversely correlated with the level of phospho(p)-Ser-GSK3αβ. Genetic or pharmacologic inhibition of Pin1 suppressed Cd-induced autophagy, but increased p-Akt-mediated p-Ser-GSK3αβ; this was reversed by overexpression of Pin1. However, suppression of GSK3αβ inhibited Cd-induced autophagy and induced apoptosis, which could be reversed by overexpression of GSK3β. The PI3K inhibitor Ly294002 blocked p-Akt-mediated increases in p-Ser-GSK3αβ and autophagy and induced apoptosis. Therefore, p-Ser-GSK3αβ can directly regulate Cd-induced autophagy, although its function is suppressed by Pin1. Collectively, the present results indicate that targeting Pin1 and GSK3αβ at the same time could be an effective therapeutic tool for Cd-induced carcinogenesis.
authors.affiliation: Department of Anesthesiology and Pain Medicine College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759, South Korea.
authors.forename: Keum-Young
authors.initials: KY
authors.lastname: So
authors.affiliation: Department of Pathology, College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759, South Korea.
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
authors.affiliation: Department of Premedicine, School of Medicine, College of Dentistry, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 501-759, South Korea. Electronic address: seonh@chosun.ac.kr.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002104:Cadmium / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D002104:Cadmium; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase
keywords: Autophagy; GSK3αβ; Oral squamous cell carcinoma; Pin1