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Inhibitors of polyamine biosynthesis decrease the expression of the metalloproteases meprin alpha and MMP-7 in

Gail L Matters1, Andrea Manni, Judith S Bond

  • 1Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, H171, Hershey, PA 17033-0850, USA.

Clinical & Experimental Metastasis
|September 20, 2005
PubMed

Insights

Alpha-difluoromethylornithine (DFMO) reduces breast cancer cell invasiveness by decreasing metalloprotease meprin alpha expression via MAP kinase signaling. This provides a mechanism for DFMO

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Metastatic breast cancer cell invasiveness is a critical factor in disease progression.
  • Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis, and its inhibition by alpha-difluoromethylornithine (DFMO) has been linked to reduced invasiveness.
  • The precise mechanism by which DFMO reduces cancer cell invasiveness remains unclear.

Purpose of the Study:

  • To investigate the effect of DFMO on metalloprotease gene expression in metastatic human breast cancer cells.
  • To elucidate the signaling pathways involved in DFMO's mechanism of action.
  • To determine the role of meprin alpha in breast cancer cell invasion.

Main Methods:

  • Treatment of MDA-MB-435 breast cancer cells with DFMO and other polyamine biosynthesis inhibitors (SAM486A).
  • Analysis of metalloprotease gene and protein expression (meprin alpha, MMP-7).
  • Investigation of the role of the MAP kinase pathway using MEK inhibitor PD98059 and assessment of invasiveness with meprin alpha inhibitor actinonin.

Main Results:

  • DFMO treatment decreased meprin alpha and MMP-7 mRNA and protein expression.
  • Concurrent treatment with putrescine partially restored meprin alpha expression.
  • MAP kinase signaling pathway activation by DFMO was demonstrated, and its inhibition reversed the decrease in meprin alpha expression.
  • Inhibition of meprin alpha reduced breast cancer cell invasiveness in vitro.

Conclusions:

  • DFMO and SAM486A decrease breast cancer cell invasiveness, at least in part, by reducing meprin alpha expression.
  • The observed effect is mediated through the MAP kinase signaling pathway.
  • Meprin alpha plays a mechanistic role in the invasiveness of metastatic breast cancer cells.

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