Abstract
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.
Highlights
Introduction published maps and institutional affilAnnually, ~22,000 new cases of ovarian cancer (OvCa) are diagnosed in the US with the majority being late stage with a very poor predicted overall survival
In the 1,457 cell lines found listed in the Cancer Cell Line Encyclopedia, leukemias and myelomas had the highest expression as measured by RNAseq among the 40 lineages examined but it is notable that the 55 OvCa cell lines were the thirteenth highest lineage in PTP4A3 expression with a mean mRNA expression level 3.8-fold higher than that seen in the human cancer line collection. qPCR profiling of established high grade serous OvCa (HGSOC) cell lines, including Kuramochi, COV362 and OVCAR4, showed 5–20 fold higher PTP4A3 gene expression versus the nonmalignant control cell line HIO-180 (Figure 1B and Supplementary Figure S1)
PTP4A3 expression is common in many cancer cell lines including
Summary
~22,000 new cases of ovarian cancer (OvCa) are diagnosed in the US with the majority being late stage with a very poor predicted overall survival. While initial responses to surgical debulking and first line chemotherapy are high, drug-resistant tumor recurrence and dissemination are common leading to death. There is a significant need to identify mechanistically new molecular targets and drugs especially for high grade serous OvCa (HGSOC). OvCa is a disease driven by the dysregulation of intracellular signaling networks and we understand many of the signaling processes by which cells transmit external information to internal effectors. Protein tyrosine kinases, which frequently become drivers of neoplastic disorders, play a prominent role. Covalent protein phosphorylation is reversible and, protein phosphatases function with kinases as non-redundant co-regulators of the overall protein phosphorylation status.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
