Androgen stimulates matrix metalloproteinase-2 expression in human prostate cancer

Endocrinology. 2003 May;144(5):1656-63. doi: 10.1210/en.2002-0157.

Abstract

Prostate growth and differentiation is androgen dependent, and increased expression of matrix metalloproteinase 2 (MMP-2) has been found in more aggressive prostate cancers. As part of our efforts to elucidate the mechanisms responsible for prostate cancer progression, we evaluated the MMP-2 expression after androgen stimulation in human prostate cancer LNCaP and LAPC-4 cells, which express a functional androgen receptor. Treatment of the cells with a synthetic androgen R1881 resulted in an increase of pro-MMP-2 expression assessed by Western blot and gelatinolytic zymography in both cell lines. R1881-stimulated pro-MMP-2 expression occurred in a dose-dependent manner, which was completely abrogated in the presence of the nonsteroid androgen antagonist bicalutamide. In accordance with the protein expression, MMP-2 promoter activity was also increased by R1881 in a cell-based luciferase reporter assay. However, R1881 treatment did not significantly affect either the pro-MMP-9 expression or its promoter activity. Although we observed an appearance of active form of MMP-2, its activator MT1-MMP was not changed after R1881 treatment. Pretreatment of the cells with inhibitors of RNA transcription, actinomycin D, or protein translation, cycloheximide, significantly suppressed R1881-induced pro-MMP-2 expression in LNCaP cells, indicating that androgen stimulates pro-MMP-2 gene expression. In addition, phosphatidylinositol 3'-kinase inhibitor, LY294002 or wortmannin, strongly inhibited R1881-induced pro-MMP-2 expression. Finally, R1881-enhanced LNCaP cell migration was clearly suppressed by LY294002 or the MMP-2 inhibitor OA-Hy in an in vitro migration assay. In conclusion, our data demonstrated that androgen stimulates pro-MMP-2 expression in LNCaP cells via phosphatidylinositol 3'-kinase-dependent androgen receptor transactivation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Movement / drug effects
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / pharmacology
  • Male
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Metribolone / pharmacology*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Prodrugs / metabolism
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / physiopathology
  • Receptors, Androgen / genetics
  • Testosterone Congeners / pharmacology*
  • Transcriptional Activation / physiology
  • Tumor Cells, Cultured

Substances

  • Chromones
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Prodrugs
  • Receptors, Androgen
  • Testosterone Congeners
  • N-hydroxy-9-octadecenamide
  • Metribolone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Matrix Metalloproteinase 2