Therapeutic relevance of the protein phosphatase 2A in cancer

// Chelsea E. Cunningham 1, * , Shuangshuang Li 1, * , Frederick S. Vizeacoumar 1, * , Kalpana Kalyanasundaram Bhanumathy 1 , Joo Sang Lee 2 , Sreejit Parameswaran 1 , Levi Furber 1 , Omar Abuhussein 3 , James M. Paul 1 , Megan McDonald 1 , Shaina D. Templeton 1 , Hersh Shukla 1 , Amr M. El Zawily 1 , Frederick Boyd 1 , Nezeka Alli 1 , Darrell D. Mousseau 4 , Ron Geyer 1 , Keith Bonham 5 , Deborah H. Anderson 5 , Jiong Yan 1 , Li-Yuan Yu-Lee 6 , Beth A. Weaver 7 , Maruti Uppalapati 1 , Eytan Ruppin 2 , Anna Sablina 8 , Andrew Freywald 1 , Franco J. Vizeacoumar 1, 3, 5 1 Department of Pathology, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada 2 Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, Maryland, MD 20742, USA 3 College of Pharmacy, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 2Z4, Canada 4 Cell Signaling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E5 Canada 5 Cancer Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, S7N 5E5, Canada 6 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 7 Department of Cell and Regenerative Biology and Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705-2275, USA 8 VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium * These authors contributed equally to this work Correspondence to: Franco J. Vizeacoumar, email: franco.vizeacoumar@usask.ca Keywords: synthetic dosage lethality, PLK1, PP2A, chromosomal instability, mitotic checkpoint Received: March 30, 2016      Accepted: August 10, 2016      Published: August 19, 2016 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.