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: Claudia Winkler, Sofie De Munter, Nele Van Dessel, Bart Lesage, Ewald Heroes, Shannah Boens, Monique Beullens, Aleyde Van Eynde, Mathieu Bollen
• Journal: Journal of cell science (J Cell Sci) Vol. 128 Issue 24 Pg. 4526-37 (Dec 15 2015) ISSN: 1477-9137 [Electronic] England
• PMID: 26542020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015. Published by The Company of Biologists Ltd.

Chemical References

• Neoplasm Proteins
• RNA-Binding Proteins
• Endoribonucleases
• Phosphoprotein Phosphatases
• Protein Phosphatase 1
• PPP1R8 protein, human

Topics

• Cell Death
• Endoribonucleases (genetics, metabolism)
• HeLa Cells
• Humans
• Mitosis
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasms (enzymology, genetics)
• Phosphoprotein Phosphatases (genetics, metabolism)
• Protein Phosphatase 1 (antagonists & inhibitors, genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)