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Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase

John S Lazo1, Kelly N Isbell2, Sai Ashish Vasa2

  • 1Department of Pharmacology, University of Virginia, Charlottesville, Virginia (J.S.L., D.C.L., E.R.S.); KeViRx, Inc., Charlottesville, Virginia (J.S.L., K.N.I., S.A.V., E.R.S.); and Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania (E.J.R., P.W.) lazo@virginia.edu.

The Journal of Pharmacology and Experimental Therapeutics
|January 10, 2023
PubMed

Insights

Protein tyrosine phosphatase type IVA member 3 (PTP4A3) inhibition with JMS-053 reduces STAT3 activation in ovarian cancer. This study highlights PTP4A3

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein tyrosine phosphatase type IVA member 3 (PTP4A3), also known as PRL-3, is an oncogenic phosphatase highly expressed in various human cancers, including ovarian cancer.
  • PTP4A3 is implicated in poor patient prognosis and is suggested to regulate STAT3, SHP-2 phosphatase, and p38 kinase signaling pathways.
  • Understanding PTP4A3's role in ovarian cancer is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the effects of the PTP4A3 inhibitor JMS-053 on STAT3, SHP-2, and p38 kinase phosphorylation in ovarian cancer cells.
  • To characterize ovarian cancer cells resistant to JMS-053 and assess their cross-resistance to conventional chemotherapeutics.
  • To elucidate the regulatory role of PTP4A3 in ovarian cancer cell signaling.

Main Methods:

  • Treatment of ovarian cancer cells with JMS-053 and assessment of STAT3, SHP-2, and p38 kinase phosphorylation.
  • Generation and characterization of JMS-053-resistant ovarian cancer cell lines (A2780 and OVCAR4).
  • Evaluation of cross-resistance to paclitaxel, cisplatin, and teniposide in resistant cell lines.

Main Results:

  • JMS-053 treatment led to a concentration- and time-dependent decrease in phospho-STAT3 (Y705) in ovarian cancer cells.
  • Conversely, JMS-053 treatment increased the phosphorylation of SHP-2 phosphatase and p38 kinase.
  • JMS-053-resistant cells showed significantly reduced basal phospho-STAT3 levels and attenuated responses to JMS-053, without cross-resistance to other chemotherapeutics.

Conclusions:

  • Chemical inhibition of PTP4A3 phosphatase activity with JMS-053 effectively decreases STAT3 activation in ovarian cancer cells.
  • JMS-053 treatment modulates the phosphorylation of SHP-2 phosphatase and p38 kinase, suggesting a role in their activation.
  • JMS-053-resistant cell lines provide valuable tools for further research into PTP4A3's function in ovarian cancer survival and signaling.

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