Role of WNT5A receptors FZD5 and RYK in prostate cancer cells
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Stefanie Thiele1,2, Ariane Zimmer1,2, Andy Göbel1,2, Tilman D. Rachner1,2, Sandra Rother3, Susanne Fuessel4, Michael Froehner4, Manfred P. Wirth4, Michael H. Muders5, Gustavo B. Baretton5, Franz Jakob6, Martina Rauner1,2 and Lorenz C. Hofbauer1,2,7
1Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Dresden, Germany
2Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany
3Institute of Materials Science, Max Bergmann Center of Biomaterials, Technische Universität Dresden, Dresden, Germany
4Department of Urology, Technische Universität Dresden, Dresden, Germany
5Institute of Pathology, Technische Universität Dresden, Dresden, Germany
6Orthopedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany
7German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
Lorenz C. Hofbauer, email: Lorenz.Hofbauer@uniklinikum-dresden.de
Keywords: prostate cancer; WNT5A; Wnt receptors; Frizzled; RYK
Received: November 06, 2017 Accepted: May 11, 2018 Published: June 05, 2018
Prostate cancer is the most common malignancy in men and has a high propensity to metastasize to bone. WNT5A has recently been implicated in the progression of prostate cancer, however, the receptors that mediate its effects remain unknown. Here, we identified Wnt receptors that are highly expressed in prostate cancer and investigated which of these receptors mediate the anti-tumor effects of WNT5A in prostate cancer in vitro.
Extensive in vitro analyses revealed that the WNT5A receptors FZD5 and RYK mediate the anti-tumor effects of WNT5A on prostate cancer cells. Knock-down of FZD5 completely abrogated the anti-proliferative effect of WNT5A in PC3 cells. In contrast, knock-down of RYK and FZD8 did not rescue the inhibition of proliferation after WNT5A overexpression. In contrast, RYK knock-down inhibited the pro-apoptotic effect of WNT5A in PC3 cells by 60%, whereas the knock-down of either FZD5 or FZD8 further stimulated apoptosis after WNT5A overexpression (by 33% and 234%, respectively). Surface plasmon resonance analysis indicated that WNT5A has a 30% stronger binding response to FZD5 than to RYK. Further investigations using a tissue microarray revealed that expression of RYK is increased in advanced prostate cancer tumor stages, but is not associated with survival of prostate cancer patients. In contrast, patients with low local FZD5 expression, in particular in combination with low WNT5A expression, showed a longer disease-specific survival.
In conclusion, WNT5A/FZD5 and WNT5A/RYK signaling are both involved in mediating the pro-apoptotic and anti-proliferative effects of WNT5A in prostate cancer.
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