title: The rotamase Pin1 is up-regulated, hypophosphorylated and required for cell cycle progression in head and neck squamous cell carcinomas.
abstract: The peptidyl-prolyl cis/trans isomerase Pin1 has been implicated in malignant transformation in multiple studies, however, little is known about its potential impact in head and neck cancer. This study evaluates the role of Pin1 in head and neck squamous cell carcinomas (HNSCCs). Pin1 expression and level of phosphorylation was evaluated by Western blot analysis and 2D-gel-electrophoresis. Pin1 was inhibited with juglone (5-hydroxy-1,4-naphthalenedione) or Pin1 specific siRNA and its influence on cell cycle checkpoint distribution was assessed by FACS analysis. Pin1 overexpression was found in HNSCC tissues and cell lines. 2D-gel-electrophoresis data pointed to Pin1 being hypophosphorylated in HNSCC cells which is consistent with overactivation of this rotamase. Inhibition of HNSCC cells with juglone or Pin1 siRNA induced the cell cycle inhibitor p21(WAF1/Cip1) with a concomitant reduction of cells in G2/M and an increased fraction of cells with fragmented DNA. Cell death did not correlate with significant levels of apoptosis in Pin1 depleted HNSCC cells. In summary, the data shows that Pin1 is overexpressed and hypophosphorylated in HNSCC, and that inhibition of Pin1 blocks cell cycle progression and triggers tumor cell death. Pin1 therefore could represent a new target for the development of improved HNSCC targeting drugs.
authors.affiliation: Dept. of Otorhinolaryngology, Head and Neck Surgery, University Hospital Giessen and Marburg, Campus Marburg D-35037, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wiegand
authors.forename: Branka
authors.initials: B
authors.lastname: Dakic
authors.forename: Ariane F E
authors.initials: AF
authors.lastname: Rath
authors.forename: Galina
authors.initials: G
authors.lastname: Makarova
authors.forename: Carolina
authors.initials: C
authors.lastname: Sterz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Meissner
authors.forename: Michael
authors.initials: M
authors.lastname: Bette
authors.forename: Jürgen
authors.initials: J
authors.lastname: Adamkiewicz
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Jochen A
authors.initials: JA
authors.lastname: Werner
authors.forename: Robert
authors.initials: R
authors.lastname: Mandic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D016022:Case-Control Studies; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000469:Alkaline Phosphatase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C005134:juglone