title: 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.
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.|Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Jen-Chih
authors.initials: JC
authors.lastname: Tseng
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan.
authors.forename: Liang-Chen
authors.initials: LC
authors.lastname: Su
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Fu
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shiaw-Der
authors.initials: SD
authors.lastname: Yang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan.|Graduate Program for Aging, China Medical University, Taichung City, Taiwan.
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002109:Caffeic Acids; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Micro-Western Array; Wnt signaling; caffeic acid phenethyl ester; metastasis; prostate cancer