CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling
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Jen-Chih Tseng1,2, Ching-Yu Lin2, Liang-Chen Su2, Hsiao-Hui Fu1, Shiaw-Der Yang1, Chih-Pin Chuu2,3
1Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
2Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan
3Graduate Program for Aging, China Medical University, Taichung City, Taiwan
Chih-Pin Chuu, email: [email protected]
Shiaw-Der Yang, email: [email protected]
Keywords: prostate cancer, metastasis, Wnt signaling, caffeic acid phenethyl ester, Micro-Western Array
Received: January 21, 2016 Accepted: May 01, 2016 Published: May 15, 2016
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.
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