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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8223-8240
Number of pages18
JournalOncotarget
Volume9
Issue number9
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Phosphoric Monoester Hydrolases
Ovarian Neoplasms
Endothelium
Neoplasms
Pericytes
Protein Tyrosine Phosphatases
Oncogene Proteins
Heterografts
Vascular Endothelial Growth Factor A
Lipopolysaccharides
Endothelial Cells
Survival
Growth
Pharmaceutical Preparations
Therapeutics

Keywords

  • Endothelium
  • Inhibitor
  • Ovarian cancer
  • Phosphatase

ASJC Scopus subject areas

  • Oncology

Cite this

McQueeney, K. E., Salamoun, J. M., Burnett, J. C., Barabutis, N., Pekic, P., Lewandowski, S. L., ... Sharlow, E. R. (2018). Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. Oncotarget, 9(9), 8223-8240. https://doi.org/10.18632/oncotarget.23787

Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. / McQueeney, Kelley E.; Salamoun, Joseph M.; Burnett, James C.; Barabutis, Nektarios; Pekic, Paula; Lewandowski, Sophie L.; Llaneza, Danielle C.; Cornelison, Robert; Bai, Yunpeng; Zhang, Zhong-Yin; Catravas, John D.; Landen, Charles N.; Wipf, Peter; Lazo, John S.; Sharlow, Elizabeth R.

In: Oncotarget, Vol. 9, No. 9, 01.01.2018, p. 8223-8240.

Research output: Contribution to journalArticle

McQueeney, KE, Salamoun, JM, Burnett, JC, Barabutis, N, Pekic, P, Lewandowski, SL, Llaneza, DC, Cornelison, R, Bai, Y, Zhang, Z-Y, Catravas, JD, Landen, CN, Wipf, P, Lazo, JS & Sharlow, ER 2018, 'Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor', Oncotarget, vol. 9, no. 9, pp. 8223-8240. https://doi.org/10.18632/oncotarget.23787
McQueeney KE, Salamoun JM, Burnett JC, Barabutis N, Pekic P, Lewandowski SL et al. Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. Oncotarget. 2018 Jan 1;9(9):8223-8240. https://doi.org/10.18632/oncotarget.23787
McQueeney, Kelley E. ; Salamoun, Joseph M. ; Burnett, James C. ; Barabutis, Nektarios ; Pekic, Paula ; Lewandowski, Sophie L. ; Llaneza, Danielle C. ; Cornelison, Robert ; Bai, Yunpeng ; Zhang, Zhong-Yin ; Catravas, John D. ; Landen, Charles N. ; Wipf, Peter ; Lazo, John S. ; Sharlow, Elizabeth R. / Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. In: Oncotarget. 2018 ; Vol. 9, No. 9. pp. 8223-8240.
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