Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer
High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) exp...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/7/969 |
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| author | John S. Lazo Elizabeth R. Sharlow Robert Cornelison Duncan J. Hart Danielle C. Llaneza Anna J. Mendelson Ettore J. Rastelli Nikhil R. Tasker Charles N. Landen Peter Wipf |
| author_facet | John S. Lazo Elizabeth R. Sharlow Robert Cornelison Duncan J. Hart Danielle C. Llaneza Anna J. Mendelson Ettore J. Rastelli Nikhil R. Tasker Charles N. Landen Peter Wipf |
| author_sort | John S. Lazo |
| collection | DOAJ |
| description | High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053. |
| first_indexed | 2024-03-10T09:53:09Z |
| format | Article |
| id | doaj.art-bd03bd9e93c14cfb8f63e736838dafd7 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T09:53:09Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-bd03bd9e93c14cfb8f63e736838dafd72023-11-22T02:33:50ZengMDPI AGBiomolecules2218-273X2021-06-0111796910.3390/biom11070969Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian CancerJohn S. Lazo0Elizabeth R. Sharlow1Robert Cornelison2Duncan J. Hart3Danielle C. Llaneza4Anna J. Mendelson5Ettore J. Rastelli6Nikhil R. Tasker7Charles N. Landen8Peter Wipf9Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USADepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USADepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USADepartment of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USADepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USAHigh grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.https://www.mdpi.com/2218-273X/11/7/969ovarian cancerprotein tyrosine phosphatasedrug target validationcell migrationIL-6drug synergy |
| spellingShingle | John S. Lazo Elizabeth R. Sharlow Robert Cornelison Duncan J. Hart Danielle C. Llaneza Anna J. Mendelson Ettore J. Rastelli Nikhil R. Tasker Charles N. Landen Peter Wipf Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer Biomolecules ovarian cancer protein tyrosine phosphatase drug target validation cell migration IL-6 drug synergy |
| title | Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer |
| title_full | Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer |
| title_fullStr | Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer |
| title_full_unstemmed | Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer |
| title_short | Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer |
| title_sort | credentialing and pharmacologically targeting ptp4a3 phosphatase as a molecular target for ovarian cancer |
| topic | ovarian cancer protein tyrosine phosphatase drug target validation cell migration IL-6 drug synergy |
| url | https://www.mdpi.com/2218-273X/11/7/969 |
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