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

Oncotarget
Kelley E McQueeneyElizabeth R Sharlow

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 cance...Continue Reading

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Citations

Feb 13, 2019·Organic & Biomolecular Chemistry·Nikhil R TaskerPeter Wipf
May 11, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kelley E McQueeneyJohn S Lazo
Oct 12, 2019·The Journal of Pharmacology and Experimental Therapeutics·John S LazoElizabeth R Sharlow
Jul 17, 2019·Bioorganic & Medicinal Chemistry Letters·Nikhil R TaskerPeter Wipf
Apr 9, 2021·Science Translational Medicine·Julia P VainonenJukka Westermarck
Jun 6, 2021·Bioorganic & Medicinal Chemistry Letters·Ettore J RastelliPeter Wipf

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Methods Mentioned

BETA
RNAseq
Thermal
thermal shift
X-ray
xenografts
GTPase
nucleotide
GTPases
nucleotide exchange
surgical resection

Software Mentioned

Discovery Studio
ImageJ
GraphPad
ImageJ Fiji
Harmony
GraphPad Prism
Maestro
HINT
ClustaW2
cBioPortal

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