Journal article
Therapeutic relevance of the protein phosphatase 2A in cancer
Oncotarget, Vol.7(38), pp.61544-61561
09/20/2016
DOI: 10.18632/oncotarget.11399
PMCID: PMC5308671
PMID: 27557495
Abstract
Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.
Details
- Title: Subtitle
- Therapeutic relevance of the protein phosphatase 2A in cancer
- Creators
- Chelsea E Cunningham - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaShuangshuang Li - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaFrederick S Vizeacoumar - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaKalpana Kalyanasundaram Bhanumathy - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaJoo Sang Lee - Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USASreejit Parameswaran - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaLevi Furber - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaOmar Abuhussein - College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 2Z4, CanadaJames M Paul - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaMegan McDonald - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaShaina D Templeton - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaHersh Shukla - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaAmr M El Zawily - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaFrederick Boyd - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaNezeka Alli - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaDarrell D Mousseau - Cell Signaling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaRon Geyer - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaKeith Bonham - Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, CanadaDeborah H Anderson - Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, CanadaJiong Yan - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaLi-Yuan Yu-Lee - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USABeth A Weaver - Department of Cell and Regenerative Biology and Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705-2275, USAMaruti Uppalapati - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaEytan Ruppin - Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USAAnna Sablina - VIB Center for the Biology of Disease, VIB, 3000 Leuven, BelgiumAndrew Freywald - Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 CanadaFranco J Vizeacoumar - Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.7(38), pp.61544-61561
- DOI
- 10.18632/oncotarget.11399
- PMID
- 27557495
- PMCID
- PMC5308671
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals LLC
- Grant note
- R01 CA140458 / NCI NIH HHS
- Language
- English
- Date published
- 09/20/2016
- Academic Unit
- Biology; Obstetrics and Gynecology
- Record Identifier
- 9984217525002771
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