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Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

John S Lazo1,2, Elizabeth R Sharlow1,2, Robert Cornelison1,2

  • 1Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.

Biomolecules
|July 2, 2021
PubMed

Insights

Targeting Protein Tyrosine Phosphatase of Regenerating Liver-3 (PTP4A3) with inhibitor JMS-053 shows promise for treating high-grade serous ovarian cancer (OvCa). PTP4A3 inhibition blocks OvCa cell migration and reduces tumor spread, supporting JMS-053 as a potential therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • High-grade serous ovarian cancer (OvCa) frequently develops drug resistance and recurs, necessitating novel therapeutic targets.
  • Bioinformatics studies identified elevated Protein Tyrosine Phosphatase of Regenerating Liver-3 (PTP4A3) expression as a marker of poor survival in OvCa patients.
  • PTP4A3 mRNA levels are significantly higher in drug-resistant and high-grade OvCa cell lines compared to normal cells.

Purpose of the Study:

  • To investigate the role of PTP4A3 in ovarian cancer progression and evaluate the therapeutic potential of PTP4A3 inhibitors.
  • To synthesize and assess analogs of the small molecule PTP4A3 inhibitor JMS-053 in OvCa cell line models.
  • To explore the impact of PTP4A3 inhibition on OvCa cell survival, migration, and in vivo dissemination.

Main Methods:

  • Synthesis and evaluation of JMS-053 analogs for PTP4A3 enzyme inhibition and OvCa cell survival.
  • Phenotypic assays using OvCa cell lines to assess the effects of JMS-053 on cell migration.
  • CRISPR/Cas9-mediated PTP4A3 depletion to confirm target specificity.
  • Combination studies with paclitaxel and in vivo xenograft models to evaluate therapeutic efficacy.

Main Results:

  • JMS-053 analogs inhibited PTP4A3 enzyme activity but did not surpass JMS-053 in reducing OvCa cell survival.
  • JMS-053, similar to PTP4A3 depletion, effectively blocked OvCa cell migration, with inhibition dependent on PTP4A3 presence.
  • JMS-053 demonstrated additive or synergistic cytotoxicity with paclitaxel in vitro and reduced tumor dissemination in vivo.

Conclusions:

  • PTP4A3 plays a critical role in ovarian cancer cell migration and dissemination.
  • The PTP4A3 inhibitor JMS-053 shows significant potential as a therapeutic agent for ovarian cancer, particularly in combination therapies.
  • Further investigation into JMS-053 is warranted for the development of novel treatments for drug-resistant and recurrent ovarian cancer.
Keywords:
IL-6cell migrationdrug synergydrug target validationovarian cancerprotein tyrosine phosphatase

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