Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor.

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

doi:10.18632/oncotarget.23787

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.

Highlights

Aberrant intracellular signaling is a recurrent feature of human cancers that is often reflected in substantial changes in pathways involving protein phosphorylation and dephosphorylation
Because an increase in PTP4A1 or PTP4A2 mRNA was not observed, we subsequently focused primarily on PTP4A3 in ovarian cancer (OvCa)
Immunohistochemical analysis of human patient tumor samples from the University of Virginia Biorepository revealed PTP4A3 protein overexpression in 45/57 (79%) primary OvCa tumors (Table 1), as well as in the tumor endothelium and pericytes (Figure 1C1D). These results provide further support that PTP4A3 overexpression occurs in human OvCa and add to its attractiveness as a candidate for pharmacological interrogation in both malignant and stromal populations within OvCa tumors

Summary

Introduction

Aberrant intracellular signaling is a recurrent feature of human cancers that is often reflected in substantial changes in pathways involving protein phosphorylation and dephosphorylation. Since protein tyrosine phosphatases (PTPs) appear to have a major role in the malignancy of cancer [2], we have initiated a program to develop small molecule probes to explore new therapeutic opportunities. Studies with patient-derived tumor samples indicate a high level of expression of protein-tyrosine phosphatase 4A (PTP4A, known as PRL) family members, and PTP4A3 in ovarian cancers [3,4,5,6]. While definitive endogenous PTP4A substrates have yet to be identified, genetic studies clearly implicate PTP4A in important cancer-associated signaling processes, thereby supporting a pivotal role for this PTP family in tumorigenesis [9,10,11,12,13]. PTP4A3 phosphatase appears to influence the function of both tumor and stromal cells

Methods

Results

Conclusion