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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)

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Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

Gopa Biswas1, Satish Srinivasan, Hindupur K Anandatheerthavarada

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

Proceedings of the National Academy of Sciences of the United States of America
|January 4, 2008
PubMed

Insights

The environmental toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) causes mitochondrial dysfunction and stress signaling, promoting tumor invasion. These effects are linked to calcineurin activation and are reversible, suggesting TCDD

Area of Science:

  • Environmental Toxicology
  • Mitochondrial Biology
  • Cancer Research

Background:

  • 2,3,7,8-tetrachlorodibenzodioxin (TCDD) is a known human carcinogen with an unclear mechanism of action.
  • Mitochondrial dysfunction and stress signaling are implicated in various diseases, including cancer.

Purpose of the Study:

  • To elucidate the mechanism by which TCDD promotes tumor progression.
  • To investigate the role of mitochondrial dysfunction and calcineurin signaling in TCDD-induced carcinogenesis.

Main Methods:

  • Treatment of C2C12 cells with TCDD.
  • Assessment of mitochondrial function (transmembrane potential, transcription, translation).
  • Measurement of cytosolic calcium levels and calcineurin (CnA) activation.
  • Evaluation of apoptosis resistance, cathepsin L expression, and cell invasion.
  • Inhibition of CnA using FK506 and CnA mRNA silencing.

Main Results:

  • TCDD disrupted mitochondrial transmembrane potential, inhibited mitochondrial transcription and translation.
  • TCDD increased cytosolic calcium, activated calcineurin (CnA), and affected NF-kappaB/Rel factors.
  • TCDD-treated cells showed apoptosis resistance, increased cathepsin L, and enhanced invasiveness.
  • FK506 and CnA silencing reversed TCDD-induced effects.

Conclusions:

  • TCDD induces mitochondrial dysfunction and stress signaling pathways similar to those in mtDNA-depleted cells.
  • TCDD promotes tumor progression by targeting mitochondrial transcription and inducing stress signaling via calcineurin.
  • These findings reveal a novel mechanism for TCDD's carcinogenic activity.

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