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Ras pathway is required for the activation of MMP-2 secretion and for the invasion of src-transformed 3Y1

A A Thant1, T T Sein, E Liu

  • 1Department of Molecular Pathogenesis, Nagoya University School of Medicine, Japan.

Oncogene
|December 22, 1999
PubMed

Insights

Ras signaling is critical for tumor invasion by activating matrix metalloproteinase-2 (MMP-2). Inhibiting Ras farnesyltransferase suppressed MMP-2 activation and invasiveness in src-transformed cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Tumor invasion is a hallmark of cancer progression.
  • Matrix metalloproteinase-2 (MMP-2) is crucial for extracellular matrix degradation during invasion.
  • The role of specific signaling pathways in MMP-2 activation and tumor invasion requires further elucidation.

Purpose of the Study:

  • To investigate the signaling pathway responsible for tumor invasion.
  • To determine the effect of Ras signaling on matrix metalloproteinase-2 (MMP-2) activation.
  • To assess the role of Ras in the invasiveness of src-transformed cells.

Main Methods:

  • Utilized dominant-negative Ras (S17N Ras) expression in src-transformed 3Y1 (SR3Y1) cells.
  • Assessed MMP-2 secretion and activation using biochemical assays.
  • Quantified cellular invasiveness via the modified Boyden Chamber assay.
  • Investigated the effects of Ras farnesyltransferase inhibitor (manumycin A), wortmannin, and TPA on MMP-2 activation.

Main Results:

  • Dominant-negative Ras (S17N Ras) expression significantly suppressed MMP-2 secretion and activation.
  • S17N Ras expression dramatically reduced the invasiveness of SR3Y1 cells.
  • Manumycin A, a Ras farnesyltransferase inhibitor, also suppressed MMP-2 activation and secretion.
  • Neither P13 kinase nor protein kinase C signaling inhibitors affected MMP-2 activation.

Conclusions:

  • Ras signaling plays a critical role in the activation of MMP-2.
  • Ras-mediated MMP-2 activation is essential for the invasiveness of src-transformed cells.
  • Targeting Ras signaling pathways may represent a therapeutic strategy to inhibit tumor invasion.

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