Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model

Abstract

Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro. We used an in vivo orthotopic xenograft mouse model with metastatic luciferase-labeled WNT5A-low DU145 cells and metastatic luciferase-labeled WNT5A-high PC3prostate cancer cells. We provide here the first evidence that Foxy-5 significantly inhibits the initial metastatic dissemination of tumor cells to regional and distal lymph nodes by 90% and 75%, respectively. Importantly, this effect was seen only with the WNT5A-low DU145 cells and not with the WNT5A-high PC3 cells. The inhibiting effect in the DU145-based model occurred despite the fact that no effects were observed on primary tumor growth, apoptosis or proliferation. These findings are consistent with and supported by the in vitro data, where Foxy-5 specifically targets invasion without affecting apoptosis or viability of WNT5A-low prostate cancer cells. To conclude, our data indicate that the WNT5A-mimicking peptide Foxy-5, which has been recently used in a phase 1 clinical trial, is an attractive candidate for complimentary anti-metastatic treatment of prostate cancer patients with tumors exhibiting absent or low WNT5A expression.

UNBS5162 inhibits the proliferation of esophageal cancer squamous cells via the PI3K/AKT signaling pathway

“…The present study is the first to illustrate that inhibition of esophageal cancer cells using a CXCL antagonist may occur via inhibition of the PI3K/AKT signaling pathway. Previous studies have indicated that cell proliferation is strongly associated with cell apoptosis in the development of numerous types of cancer (31)(32)(33)(34)(35). In the present study, a reduction in cell proliferation was accompanied by increased apoptosis following treatment with UNBS5162, as determined by CCK-8 assays, flow cytometry and alterations in the expression of apoptosis-associated proteins.…”

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

“…Foxy-5 is a hexapeptide mimic of Wnt5a which is synthesized to possess Wnt5a-like properties that can impair cancer cell migration. After a successful phase 1 study in colon/breast/prostate cancer patients showing no toxicity, phase 1b trials are ongoing and expected to show promising therapeutic value (112). Also, peptides derived by modifying the Wnt5a ligand sequence have shown the capability to mimic the Wnt5a molecule.…”

Recent Advances in Prostate Cancer Treatment and Drug Discovery

“…Preclinical data show the involvement of both canonical and non-canonical WNT signaling in prostate cancer. A tumor-suppressive role has also been described for some members of the WNT pathway and early clinical studies are currently ongoing in different indications including metastatic prostate cancer to evaluate a peptide mimetic of WNT-5A which showed promising results in an orthotopic prostate cancer mouse model [ 74 ]. Deregulation of both the PI3K and WNT pathways further enhances prostate tumor growth due to aberrant downstream mTOR signaling [ 75 ].…”