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Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion

G Amuthan1, G Biswas, S Y Zhang

  • 1Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

The EMBO Journal
|April 11, 2001
PubMed

Insights

Mitochondrial stress, from DNA damage or inhibitors, triggers cell invasion and tumor markers like cathepsin L and TGF-beta. Restoring mitochondrial DNA reduces these aggressive traits, revealing a new cancer progression pathway.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Cancer Research

Background:

  • Mitochondrial stress, including genetic and metabolic insults, was previously shown to increase cytoplasmic-free Ca(2+).
  • This stress response links mitochondrial dysfunction to cellular signaling pathways.

Purpose of the Study:

  • To investigate if mitochondria-to-nucleus stress signaling induces invasive phenotypes in non-invasive cells.
  • To identify molecular mechanisms linking mitochondrial stress to cancer progression and metastasis.

Main Methods:

  • Inducing mitochondrial genetic (DNA depletion) and metabolic (inhibitor treatment) stress in C2C12 myoblasts and A549 cells.
  • Assessing cell invasion through Matrigel and xenotransplants in Scid mice.
  • Measuring expression of tumor markers (cathepsin L, TGF-beta) and activation of Ca(2+)-dependent protein kinase C (PKC).
  • Evaluating invasive properties and marker expression in cells with restored mitochondrial DNA.

Main Results:

  • Mitochondrial stress induced invasive phenotypes in C2C12 and A549 cells.
  • Overexpression of tumor markers cathepsin L and TGF-beta was observed under stress.
  • Stressed C2C12 myoblasts showed a 4- to 6-fold increase in invasion.
  • Activation of PKC correlated with increased cathepsin L expression and cell invasiveness.
  • Restoring mitochondrial DNA partially reverted cells to a non-invasive state.

Conclusions:

  • Mitochondria-to-nucleus stress signaling promotes cell invasion and upregulates tumor markers.
  • PKC activation plays a role in mediating the invasive properties induced by mitochondrial stress.
  • Mitochondrial DNA damage and membrane damage can contribute to tumor progression and metastasis via this pathway.

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