CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling

Abstract

Prostate cancer (PCa) was the fifth most common cancer overall in the world. More than 80% of patients died from PCa developed bone metastases. Caffeic acid phenethyl ester (CAPE) is a main bioactive component of honeybee hive propolis. Transwell and wound healing assays demonstrated that CAPE treatment suppressed the migration and invasion of PC-3 and DU-145 PCa cells. Gelatin zymography and Western blotting indicated that CAPE treatment reduced the abundance and activity of MMP-9 and MMP-2. Analysis using Micro-Western Array (MWA), a high-throughput antibody-based proteomics platform with 264 antibodies detecting signaling proteins involved in important pathways indicated that CAPE treatment induced receptor tyrosine kinase-like orphan receptor 2 (ROR2) in non-canonical Wnt signaling pathway but suppressed abundance of β-catenin, NF-κB activity, PI3K-Akt signaling, and epithelial-mesenchymal transition (EMT). Overexpression or knockdown of ROR2 suppressed or enhanced cell migration of PC-3 cells, respectively. TCF-LEF promoter binding assay revealed that CAPE treatment reduced canonical Wnt signaling. Intraperitoneal injection of CAPE reduced the metastasis of PC-3 xenografts in tail vein injection nude mice model. Immunohistochemical staining demonstrated that CAPE treatment increased abundance of ROR2 and Wnt5a but decreased protein expression of Ki67, Frizzle 4, NF-κB p65, MMP-9, Snail, β-catenin, and phosphorylation of IκBα. Clinical evidences suggested that genes affected by CAPE treatment (CTNNB1, RELA, FZD5, DVL3, MAPK9, SNAl1, ROR2, SMAD4, NFKBIA, DUSP6, and PLCB3) correlate with the aggressiveness of PCa. Our study suggested that CAPE may be a potential therapeutic agent for patients with advanced PCa.

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

“…Despite the fact that MMPs are key regulators of invasion in prostate cancer cells [ 43 – 45 ], our results indicate that MMP9 is not a target of Foxy-5 in DU145 prostate cancer cells, which is in contrast to breast cancer cells [ 40 ]. Importantly, our present results lend direct support to recent findings implicating WNT5A in the suppression of prostate cancer metastases through a complex network of signaling proteins, including Snail, Cyclin D1 and c-Myc [ 46 ]. Moreover, WNT5A may be involved in the regulation of prostate cancer cells adhesion, as already shown in several other tumors [ 31 , 47 – 49 ].…”

“…WNT5A is known to elicit non-canonical signaling upon binding to different receptor/co-receptor complexes, including ROR-2 and Frizzled receptors [ 50 , 51 ]. Both DU145 and PC3 cell lines express ROR-2 [ 46 ] and it is known that the WNT5A associated Frizzled receptors Fzd-2, Fzd-3, Fzd-5 and Fzd-7 are also expressed on these cells as well as on other PCa cell lines [ 46 , 52 – 54 ]. In addition, the Fzd-5 receptor, a commonly described receptor for WNT5A, has an even higher expression (at both mRNA and protein level) in PC3 cells compared with DU145 cells [ 55 ].…”

Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis

“…Although not all the key players in the development of bone metastases are yet known, multiple molecules and signaling pathways appear to be important for metastasis. Indeed, in addition to the IGF pathway, NF-kB, matrix metalloproteases, and the Wnt, stromal cell-derived factor 1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) and PI3K/AKT signaling axes may also play key roles in the development and progression of bone metastases (39)(40)(41)(42)(43)(44)(45)(46).…”

Caffeic acid phenethyl ester (CAPE): pharmacodynamics and potential for therapeutic application

“…Its activation leads to NF-κB activation and has been reported to have a role in type 2 diabetes (Carracedo and Pandolfi 2008). Another study shows that CAPE suppressed canonical Wnt signaling of prostate cancer cells, reducing their invasiveness (Tseng et al 2016). Wnt signaling pathway activation is related to carcinogenesis and promotion of metastasis (Zhan et al 2017).…”