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Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase

Takeharu Sakamoto1, Motoharu Seiki2

  • 1Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Cancer Science
|March 8, 2017
PubMed

Insights

Membrane-type 1 matrix metalloproteinase (MT1-MMP) impacts cancer by both degrading the extracellular matrix and non-proteolytically activating hypoxia-inducible factors (HIFs). This dual activity promotes tumor growth and metastasis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) is crucial in invasive and proliferative cells, including cancer and stromal cells.
  • MT1-MMP's proteolytic activity modifies the cellular microenvironment, impacting cancer cell proliferation, invasion, and metastasis.
  • MT1-MMP also exhibits non-proteolytic functions, notably inhibiting hypoxia-inducible factor (HIF) suppression.

Purpose of the Study:

  • To review the mechanisms by which MT1-MMP activates HIF.
  • To summarize the effects of MT1-MMP-mediated HIF activation on cancer and stromal cells.
  • To highlight the integrated roles of MT1-MMP's proteolytic and non-proteolytic activities in tumor malignancy.

Main Methods:

  • Literature review of recent findings on MT1-MMP and HIF activation.
  • Analysis of studies investigating MT1-MMP's proteolytic and non-proteolytic functions.
  • Examination of research on HIF target gene expression and the Warburg effect in cancer.

Main Results:

  • MT1-MMP activates HIF via interaction with Mint3, bypassing oxygen-dependent suppression.
  • Elevated HIF activity driven by MT1-MMP contributes to the Warburg effect in cancer cells.
  • MT1-MMP's dual activities are essential for tumor formation and progression, as demonstrated by suppressed tumor growth in mice upon intervention.

Conclusions:

  • MT1-MMP plays a critical role in cancer malignancy through both enzymatic and non-enzymatic pathways.
  • MT1-MMP-mediated HIF activation is a key mechanism promoting cancer cell metabolism and survival.
  • Targeting MT1-MMP's integrated functions offers potential therapeutic strategies against cancer.
Keywords:
CancerMT1-MMPhypoxiasignal transductiontumor microenvironment

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