Role of WNT5A receptors FZD5 and RYK in prostate cancer cells

Abstract

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.

WLS-Wnt signaling promotes neuroendocrine prostate cancer

“…Wnt5A is the most significantly activated Wnt from our RNA-seq data in ENZ R NEPC cells, raising the possibility that Wnt5A is the dominant Wnt mediating WLS-Wnt signaling in NEPC. Wnt5A exhibits both tumor promoting and suppressive roles in PC, which likely depends on the combination and availability of different Wnt receptors for alterations in signaling output (Lee et al, 2018a;Ren et al, 2019;Thiele et al, 2018). We suspect that elevated expression of ROR2 in NEPC cells could release Wnt5A from association with other Wnt receptors, making it more prone to support NEPC growth.…”

Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes

“…However, the role of WNT5A is complex and depending on other cell characteristics. This could be the reason explaining that opposite effects have been described in other cancer cells (50)(51)(52). This is a common feature of WNTs where a major determinant of the effects is the cellular context concerning factors such as the expressed repertoire of receptors and signal transducers (13).…”

Construction and Validation of a Robust Cancer Stem Cell-Associated Gene Set-Based Signature to Predict Early Biochemical Recurrence in Prostate Cancer

“…FDZ5 is a member of “frizzled” gene family and is believed to be the receptor for the Wnt5A ligand. Previous studies suggested that FDZ5 involved in mediating the proapoptotic and antiproliferative effects of WNT5A in prostate cancer [ 23 ]. GREM1 expression is found in many cancers and is thought to play important roles in regulative cell proliferation and survival of PCa [ 24 ].…”