title: Therapeutic relevance of the protein phosphatase 2A in cancer.
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.
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Chelsea E
authors.initials: CE
authors.lastname: Cunningham
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Vizeacoumar
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Kalpana Kalyanasundaram
authors.initials: KK
authors.lastname: Bhanumathy
authors.affiliation: Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USA.
authors.forename: Joo Sang
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Sreejit
authors.initials: S
authors.lastname: Parameswaran
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Levi
authors.initials: L
authors.lastname: Furber
authors.affiliation: College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 2Z4, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: Abuhussein
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: James M
authors.initials: JM
authors.lastname: Paul
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: McDonald
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Shaina D
authors.initials: SD
authors.lastname: Templeton
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Hersh
authors.initials: H
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Amr M
authors.initials: AM
authors.lastname: El Zawily
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Boyd
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Nezeka
authors.initials: N
authors.lastname: Alli
authors.affiliation: Cell Signaling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Mousseau
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Ron
authors.initials: R
authors.lastname: Geyer
authors.affiliation: Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Bonham
authors.affiliation: Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.affiliation: Department of Cell and Regenerative Biology and Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705-2275, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Weaver
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Maruti
authors.initials: M
authors.lastname: Uppalapati
authors.affiliation: Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USA.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Sablina
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.affiliation: Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada.|College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 2Z4, Canada.|Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada.
authors.forename: Franco J
authors.initials: FJ
authors.lastname: Vizeacoumar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002193:Cantharidin / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056286:Retinoblastoma Binding Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D002193:Cantharidin; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C000606393:RB1 protein, human
keywords: PLK1; PP2A; chromosomal instability; mitotic checkpoint; synthetic dosage lethality