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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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Autores principales: Lazo, John S., Sharlow, Elizabeth R., Cornelison, Robert, Hart, Duncan J., Llaneza, Danielle C., Mendelson, Anna J., Rastelli, Ettore J., Tasker, Nikhil R., Landen, Charles N., Wipf, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329922/
https://www.ncbi.nlm.nih.gov/pubmed/34209460
http://dx.doi.org/10.3390/biom11070969
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author Lazo, John S.
Sharlow, Elizabeth R.
Cornelison, Robert
Hart, Duncan J.
Llaneza, Danielle C.
Mendelson, Anna J.
Rastelli, Ettore J.
Tasker, Nikhil R.
Landen, Charles N.
Wipf, Peter
author_facet Lazo, John S.
Sharlow, Elizabeth R.
Cornelison, Robert
Hart, Duncan J.
Llaneza, Danielle C.
Mendelson, Anna J.
Rastelli, Ettore J.
Tasker, Nikhil R.
Landen, Charles N.
Wipf, Peter
author_sort Lazo, John S.
collection PubMed
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.
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spelling pubmed-83299222021-08-04 Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer Lazo, John S. Sharlow, Elizabeth R. Cornelison, Robert Hart, Duncan J. Llaneza, Danielle C. Mendelson, Anna J. Rastelli, Ettore J. Tasker, Nikhil R. Landen, Charles N. Wipf, Peter Biomolecules Article 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. MDPI 2021-06-30 /pmc/articles/PMC8329922/ /pubmed/34209460 http://dx.doi.org/10.3390/biom11070969 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lazo, John S.
Sharlow, Elizabeth R.
Cornelison, Robert
Hart, Duncan J.
Llaneza, Danielle C.
Mendelson, Anna J.
Rastelli, Ettore J.
Tasker, Nikhil R.
Landen, Charles N.
Wipf, Peter
Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329922/
https://www.ncbi.nlm.nih.gov/pubmed/34209460
http://dx.doi.org/10.3390/biom11070969
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