Oncotarget

Priority Research Papers:

Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor

Kelley E. McQueeney, Joseph M. Salamoun, James C. Burnett, Nektarios Barabutis, Paula Pekic, Sophie L. Lewandowski, Danielle C. Llaneza, Robert Cornelison, Yunpeng Bai, Zhong-Yin Zhang, John D. Catravas, Charles N. Landen, Peter Wipf, John S. Lazo, Elizabeth R. Sharlow _

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Oncotarget. 2018; 9:8223-8240. https://doi.org/10.18632/oncotarget.23787

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Abstract

Kelley E. McQueeney1, Joseph M. Salamoun2, James C. Burnett2, Nektarios Barabutis3, Paula Pekic1, Sophie L. Lewandowski1, Danielle C. Llaneza4, Robert Cornelison4, Yunpeng Bai5, Zhong-Yin Zhang5, John D. Catravas3, Charles N. Landen4, Peter Wipf2, John S. Lazo1 and Elizabeth R. Sharlow1

1 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA

2 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

3 Frank Reidy Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA

4 Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA

5 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA

Correspondence to:

Elizabeth R. Sharlow, email:

John S. Lazo, email:

Keywords: phosphatase, ovarian cancer, endothelium, inhibitor

Received: October 05, 2017 Accepted: November 25, 2017 Published: December 30, 2017

Abstract

Overexpression of protein tyrosine phosphatase PTP4A oncoproteins is common in many human cancers and is associated with poor patient prognosis and survival. We observed elevated levels of PTP4A3 phosphatase in 79% of human ovarian tumor samples, with significant overexpression in tumor endothelium and pericytes. Furthermore, PTP4A phosphatases appear to regulate several key malignant processes, such as invasion, migration, and angiogenesis, suggesting a pivotal regulatory role in cancer and endothelial signaling pathways. While phosphatases are attractive therapeutic targets, they have been poorly investigated because of a lack of potent and selective chemical probes. In this study, we disclose that a potent, selective, reversible, and noncompetitive PTP4A inhibitor, JMS-053, markedly enhanced microvascular barrier function after exposure of endothelial cells to vascular endothelial growth factor or lipopolysaccharide. JMS-053 also blocked the concomitant increase in RhoA activation and loss of Rac1. In human ovarian cancer cells, JMS-053 impeded migration, disrupted spheroid growth, and decreased RhoA activity. Importantly, JMS-053 displayed anticancer activity in a murine xenograft model of drug resistant human ovarian cancer. These data demonstrate that PTP4A phosphatases can be targeted in both endothelial and ovarian cancer cells, and confirm that RhoA signaling cascades are regulated by the PTP4A family.


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