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Iron regulates MT1-MMP-mediated proMMP-2 activation and cancer cell invasion

Risa Takatsuka1, Minoru Terashima2, Akihiko Ishimura1

  • 1Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.

Biochemical and Biophysical Research Communications
|December 7, 2024
PubMed

Insights

Excess cellular iron fuels cancer growth and spread by increasing MT1-MMP activity, which activates proMMP-2. Iron reduction inhibits this cancer invasion pathway.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Cellular Metabolism

Background:

  • Cellular iron is vital for physiological processes.
  • Imbalanced iron homeostasis contributes to cancer development and metastasis.
  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) drives tumor invasion by degrading the extracellular matrix.

Purpose of the Study:

  • To investigate the role of cellular iron in regulating MT1-MMP activity and cancer cell invasion.
  • To elucidate the mechanism by which iron influences MT1-MMP-mediated proMMP-2 activation.

Main Methods:

  • Manipulating cellular iron levels (depletion and loading) in cancer cells.
  • Assessing MT1-MMP expression and activity.
  • Measuring proMMP-2 activation.
  • Evaluating cancer cell invasion in vitro.
  • Utilizing antioxidant treatment and iron chelators (deferasirox).

Main Results:

  • Iron depletion downregulated MT1-MMP expression and inhibited proMMP-2 activation in cancer cells.
  • Iron loading upregulated MT1-MMP expression and stimulated MT1-MMP-containing extracellular vesicle secretion, enhancing proMMP-2 activation.
  • Antioxidant treatment reversed iron-induced proMMP-2 activation.
  • Deferasirox suppressed cancer cell invasion but not fibroblast invasion.

Conclusions:

  • Cellular iron accumulation promotes cancer cell invasion by activating the MT1-MMP/MMP-2 axis.
  • MT1-MMP expression and activity are iron-dependent.
  • Targeting iron metabolism could be a therapeutic strategy against cancer metastasis.
Keywords:
ECMInvasionIronMT1-MMPMigration

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