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PTN signaling: Components and mechanistic insights in human ovarian cancer
Geetika Sethi1,2, Youngjoo Kwon1, Rebecca J Burkhalter1
1Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
Abstract:
Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian tumors.
Insights
Targeting pleiotrophin (PTN) and its receptor protein tyrosine phosphatase receptor Z1 (PTPRZ1) shows promise for epithelial ovarian cancer (EOC) treatment. This pathway, including MAPK signaling, is crucial for EOC cell survival and presents a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted therapies offer advantages over traditional chemotherapy for ovarian cancer.
- Pleiotrophin (PTN) was previously identified as a molecular vulnerability in epithelial ovarian cancer (EOC).
- The role of the PTN-PTPRZ1 pathway in ovarian cancer pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the expression and role of PTN and its receptor PTPRZ1 in epithelial ovarian cancer (EOC).
- To determine the downstream signaling pathways affected by PTN in EOC.
- To provide a rationale for targeting the PTN-PTPRZ1 pathway in ovarian cancer treatment.
Main Methods:
- Assessed PTN and PTPRZ1 expression in EOC cell lines and tumor tissues.
- Utilized siRNA-mediated gene silencing to investigate the function of PTN and PTPRZ1 in EOC cells.
- Performed expression profiling of survival-related genes and computational mapping to identify downstream effectors.
Main Results:
- PTN is expressed, secreted by EOC cells, and elevated in tumor tissues and patient serum.
- PTPRZ1 is upregulated in serous ovarian tumors and essential for EOC cell viability, inducing apoptosis upon silencing.
- MAPK signaling pathway members were identified as likely effectors of PTN signaling in EOC.
Conclusions:
- PTN and PTPRZ1 signaling are significant in epithelial ovarian cancer pathogenesis.
- PTN and PTPRZ1 represent potential therapeutic targets for ovarian cancer.
- MAPK inhibitors warrant clinical evaluation for ovarian tumors expressing PTN and/or PTPRZ1.
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