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.