MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer

L. Xu, S. Chen, R. C. Bergan

Research output: Contribution to journalArticle

151 Scopus citations

Abstract

Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor β (TGFβ)-mediated increases in cell invasion are dependent upon activation of the serine/ threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGFβ treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wildtype MAPKAPK2 and HSP27 both increased TGFβ-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGFβ-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGFβ-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGFβ-mediated increases in MMP-2 and cell invasion in human prostate cancer.

Original languageEnglish (US)
Pages (from-to)2987-2998
Number of pages12
JournalOncogene
Volume25
Issue number21
DOIs
StatePublished - May 18 2006

Keywords

  • Heat-shock protein 27
  • Invasion
  • Matrix metalloproteinase-2
  • Mitogen-activated protein kinase-activated protein kinase 2
  • Prostate cancer
  • Transforming growth factor β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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