Decorin Suppresses Prostate Tumor Growth through Inhibition of Epidermal Growth Factor and Androgen Receptor Pathways

Abstract

Epidermal growth factor receptor (EGFR) and androgen receptor (AR) pathways play pivotal roles in prostate cancer progression. Therefore, agents with dual-targeting ability may have important therapeutic potential. Decorin, a proteoglycan present in the tumor microenvironment, is known to regulate matrix assembly, growth factor binding, and receptor tyrosine kinase activity. Here, we show that in prostate-specific Pten(P-/-) mice, a genetically defined, immune-competent mouse model of prostate cancer, systemic delivery of decorin inhibits tumor progression by targeting cell proliferation and survival pathways. Moreover, in human prostate cancer cells, we show that decorin specifically inhibits EGFR and AR phosphorylation and cross talk between these pathways. This prevents AR nuclear translocation and inhibits the production of prostate specific antigen. Further, the phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathway is suppressed leading to tumor cell apoptosis. Those findings highlight the effectiveness of decorin in the presence of a powerful genetic cancer risk and implicate decorin as a potential new agent for prostate cancer therapy by targeting EGFR/AR-PI3K-Akt pathways.

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…Numerous preclinical studies aiming to develop novel therapies for preventing or treating PCs have led to the identification of a variety of potential chemopreventive and chemotherapeutic agents, including natural and dietary compounds and pharmacological agents or gene therapies, to eradicate the total tumor cell mass, including PC stem/progenitor cells and their progenies (76,137,(185)(186)(187)(188)(189)(190)(191)(192)(193)(194)(195)(196)(197)(198).…”

“…Some preclinical investigations aiming to develop novel strategies to prevent PC formation or disease progression have aimed to establish the chemopreventive and anticarcinogenic effects induced by diverse dietary compounds using TRAMP and PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200).…”

“…In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200). Of therapeutic interest, it has been shown that different dietary compounds, including curcumin, lycopene, silibinin, feeding of dibenzoylmethane, green tea polyphenols, genistein, α-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib and sulindax, or their chemical derivatives, significantly decreased the incidence of PIN lesions and PC formation and/or delayed the disease progression in the TRAMP or PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). The anticarcinogenic effects of these dietary agents, alone or in combination, were mediated at least in part through downregulation of diverse growth factor cascades, including EGFR and sonic hedgehog and their downstream signaling elements such as PI3K/Akt and NF-κB in cancer cells (137,(187)(188)(189)(190)(191)(192)(193)(194)198).…”

“…Of therapeutic interest, it has been shown that different dietary compounds, including curcumin, lycopene, silibinin, feeding of dibenzoylmethane, green tea polyphenols, genistein, α-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib and sulindax, or their chemical derivatives, significantly decreased the incidence of PIN lesions and PC formation and/or delayed the disease progression in the TRAMP or PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). The anticarcinogenic effects of these dietary agents, alone or in combination, were mediated at least in part through downregulation of diverse growth factor cascades, including EGFR and sonic hedgehog and their downstream signaling elements such as PI3K/Akt and NF-κB in cancer cells (137,(187)(188)(189)(190)(191)(192)(193)(194)198). For instance, several botanic compounds such as genistein, apigenin, baicalein, curcumin, epigallocatechin 3-gallate, quercetin and resveratrol have been reported to inhibit the hedgehog cascade and GLI-1 expression and suppress the in vitro growth of PC cell lines such as androgen-dependent LNCaP and AI PC3 cells and disease progression in the TRAMP model of PC (191).…”

Decreased plasma decorin levels following acute ischemic stroke: Correlation with MMP-2 and differential expression in TOAST subtypes

“…During the past decade, accumulating evidence has suggested that DCN interacts with a variety of biological molecules, including type I collagen, fibronectin, thrombospondin, epidermal growth factor receptors (EGF-Rs), insulin-like growth factor-1 receptors (IGF-1Rs), platelet-derived growth factor (PDGF), complement C1q and MMPs, particularly MMP-2 and MMP-9 (5)(6)(7)(8). These factors are involved in matrix assembly and may be involved in the regulation of fundamental biological functions, including cell attachment, migration and proliferation (9)(10)(11)(12).…”