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Published on: November 2, 2014
Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence
Benjamin G Bitler1, Jasmine P Nicodemus, Hua Li
1Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Abstract:
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a noncanonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We show that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; P = 0.039) or fallopian tube epithelium (n = 28; P < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (P = 0.003) and predicts shorter overall survival in EOC patients (P = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A/promyelocytic leukemia senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.
Insights
Loss of Wnt5a expression is linked to poor outcomes in epithelial ovarian cancer (EOC). Restoring Wnt5a induces cellular senescence, inhibiting EOC cell growth and offering a potential new therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Epithelial ovarian cancer (EOC) is a highly lethal gynecologic malignancy requiring novel therapeutic strategies.
- Cellular senescence, a tumor suppression mechanism, is emerging as a promising target for cancer therapy.
- Wnt5a, a noncanonical Wnt ligand, has context-dependent roles in cancer, necessitating investigation into its function in EOC.
Purpose of the Study:
- To investigate the role of Wnt5a in regulating cellular senescence in epithelial ovarian cancer (EOC) cells.
- To determine the correlation between Wnt5a expression levels and clinical outcomes in EOC patients.
- To explore the therapeutic potential of Wnt5a restoration in EOC treatment.
Main Methods:
- Quantitative analysis of Wnt5a expression in human EOC cell lines, primary EOC tissues, normal ovarian surface epithelium, and fallopian tube epithelium.
- Correlation analysis between Wnt5a expression levels, tumor stage, and patient survival.
- In vitro and in vivo experiments involving restoration of Wnt5a expression in EOC cells and assessment of proliferation and senescence.
- Mechanistic studies to elucidate the signaling pathways involved in Wnt5a-induced senescence.
Main Results:
- Wnt5a expression is significantly lower in EOC cell lines and primary tumors compared to normal epithelial tissues.
- Reduced Wnt5a levels correlate with advanced tumor stage and predict shorter overall survival in EOC patients.
- Restoration of Wnt5a inhibits EOC cell proliferation in vitro and in vivo.
- Wnt5a antagonizes Wnt/β-catenin signaling and induces senescence via the A/promyelocytic leukemia pathway.
Conclusions:
- Loss of Wnt5a is a predictor of poor prognosis in epithelial ovarian cancer.
- Wnt5a suppresses EOC growth by inducing cellular senescence.
- Reconstituting Wnt5a signaling represents a potential novel therapeutic strategy for EOC.
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