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.
Highlights
Prostate cancer (PCa) ranks the 5th most common cancer in the world
We discovered that Caffeic acid phenethyl ester (CAPE) treatment suppressed migration and invasion of PC-3 and DU-145 PCa cells via induction of non-canonical Wnt signaling and inhibition of proteins involved in epithelial-mesenchymal transition (EMT)
Knockdown of receptor 2 (ROR2) by shRNA blocked the suppressive effects of CAPE on prostate cancer cell migration. These results indicated that CAPE treatment suppressed prostate cancer cell migration via induction of ROR2
Summary
Surgery is effective for localized PCa. Approximately 15–35% of PCa patient eventually develop metastasis. Bone is the most frequent site of distant prostate cancer metastases, approximately 90% of patients with metastatic PCa have skeletal lesions. Bone metastases depend on dynamic crosstalk between PCa cells, bone marrow microenvironment, osteoblasts, and osteoclasts [1]. Hormone ablation therapy is the standard treatment for metastatic PCa. The majority of PCa patients receiving androgen ablation therapy will develop castration-resistant prostate cancer (CRPC) within 1–3 years with a median survival time of 1–2 years. PCa bone metastases form osteoblastic lesions, which is characterized by www.impactjournals.com/oncotarget increased bone production [3]. Several proteins involved in Wnt signaling are involved in prostate tumor-induced osteoblastic activity [4], indicating that small molecular targeting Wnt signaling may be effective intervention for PCa metastasis
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