title: The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth.
abstract: The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitotic-arrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe.
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Claudia
authors.initials: C
authors.lastname: Winkler
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: De Munter
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Van Dessel
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Lesage
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Ewald
authors.initials: E
authors.lastname: Heroes
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Shannah
authors.initials: S
authors.lastname: Boens
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Monique
authors.initials: M
authors.lastname: Beullens
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Aleyde
authors.initials: A
authors.lastname: Van Eynde
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven B-3000, Belgium Mathieu.Bollen@med.kuleuven.be.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
mesh_terms: D016923:Cell Death; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C097081:PPP1R8 protein, human
keywords: Cell death; Mitotic catastrophe; NIPP1; Protein phosphatase-1; Tumor growth