Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases. (26th October 2015)

• Record Type: Journal Article
• Authors: Romero, Diana; Al-Shareef, Zainab; Gorroño-Etxebarria, Irantzu; Atkins, Stephanie; Turrell, Frances; Chhetri, Jyoti; Bengoa-Vergniory, Nora; Zenzmaier, Christoph; Berger, Peter; Waxman, Jonathan; Kypta, Robert
• Is Part Of: Carcinogenesis. Volume 37:Number 1(2016:Jan.)
• Page Start: 18
• Page End: 29
• Publication Date: 2015-10-26
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgv153
• Languages: English
• ISSNs: 0143-3334

Abstract

Summary: Matrix metalloproteases (MMPs) play important roles in tissue morphogenesis and tumor cell invasion. Here, we show that MMPs play roles in the cellular responses to Dickkopf-3 during prostate epithelial cell acinar morphogenesis and TGF-β-dependent prostate cancer cell invasion. Abstract : Dickkopf-3 (Dkk-3) is a secreted protein whose expression is downregulated in many types of cancer. Endogenous Dkk-3 is required for formation of acini in 3D cultures of prostate epithelial cells, where it inhibits transforming growth factor (TGF)-β/Smad signaling. Here, we examined the effects of Dkk-3 on the expression and activity of matrix metalloproteases (MMPs), which mediate the effects of TGF-β on extracellular matrix disassembly during tissue morphogenesis and promote invasion of tumor cells. Silencing of Dkk-3 in prostate epithelial cells resulted in increased expression and enzyme activity of MMP-2 and MMP-9. Inhibition of MMP-9 partially restored normal acinar morphogenesis in Dkk-3-silenced RWPE-1 prostate epithelial cells. In PC3 prostate cancer cells, Dkk-3 inhibited TGF-β-dependent migration and invasion. Inhibition was mediated by the Dkk-3 C-terminal cysteine-rich domain (Cys2), which also inhibited TGF-β-induced expression of MMP9 and MMP13. In contrast, Dkk-3, but not Cys2, increased formation of normal acini in Dkk-3-silenced prostate epithelial cells. These observations highlight a role for Dkk-3 in modulating TGF-β/MMP signals in the prostate, and suggest that the Dkk-3 Cys2 domain can be used as a basis for therapies that target the tumor promoting effects of TGF-β signaling in advanced prostate cancer.