Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases.
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.
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK, r.kypta@imperial.ac.uk.
Diana
D
Romero
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Zainab
Z
Al-Shareef
Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, 48160 Spain and.
Irantzu
I
Gorroño-Etxebarria
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Stephanie
S
Atkins
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Frances
F
Turrell
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Jyoti
J
Chhetri
Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, 48160 Spain and Present address: Department of Physiology, Anatomy and Genetics, Oxford University, Oxford OX1 3QX, UK.
Nora
N
Bengoa-Vergniory
Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck A6020, Austria Present address: University of Applied Sciences Tyrol, Innsbruck A6020, Austria.
Christoph
C
Zenzmaier
Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck A6020, Austria.
Peter
P
Berger
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Jonathan
J
Waxman
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK, Cell Biology and Stem Cells Unit, CIC bioGUNE, Bilbao, 48160 Spain and r.kypta@imperial.ac.uk.
Robert
R
Kypta
D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D045744:Cell Line, Tumor; D018925:Chemokines; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016212:Transforming Growth Factor beta; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9