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p53 suppresses Src-induced podosome and rosette formation and cellular invasiveness through the upregulation of

Utpal K Mukhopadhyay1, Robert Eves, Lilly Jia

  • 1Department of Biochemistry, Queen's University, Kingston, ON, Canada.

Molecular and Cellular Biology
|April 8, 2009
PubMed

Insights

The tumor suppressor p53 inhibits cancer cell migration and invasion by downregulating podosome formation. This study reveals p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor p53's role in preventing tumor initiation is established.
  • p53's function in inhibiting tumor progression and metastasis is known, but its specific mechanisms are unclear.
  • The impact of p53 on cell migration and invasion, key steps in metastasis, requires further investigation.

Purpose of the Study:

  • To investigate the role of p53 in suppressing Src-induced cell migration and invasion.
  • To elucidate the molecular mechanisms by which p53 affects cell motility and extracellular matrix degradation.
  • To identify novel pathways regulated by p53 that control cancer cell invasion and metastasis.

Main Methods:

  • Utilized vascular smooth muscle cells and NIH 3T3 fibroblast cells.
  • Manipulated p53 expression and function using overexpression and short hairpin RNA (shRNA) knockdown.
  • Assessed podosome/rosette formation, extracellular matrix digestion, cell migration, and invasion assays.
  • Analyzed p53 and caldesmon expression in Src-transformed cells.

Main Results:

  • p53 overexpression or activation suppressed Src-induced podosome formation, ECM digestion, migration, and invasion.
  • p53 knockdown or inactivation exacerbated these Src-driven phenotypes.
  • Cells with constitutively active Src showed downregulated p53 expression and function, correlating with aggressive invasion.
  • p53 upregulated caldesmon, an actin-binding protein inhibiting podosome formation; caldesmon knockdown diminished p53's suppressive effects.

Conclusions:

  • p53 acts as a potent suppressor of Src-induced cell migration, invasion, and extracellular matrix digestion.
  • p53 exerts its anti-metastatic effects, in part, by upregulating caldesmon, which inhibits podosome formation.
  • This study identifies a novel mechanism involving caldesmon and podosomes through which p53 functions as an anti-metastasis agent.

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