Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling
Abstract
The environmental toxin 2,3,7,8-tetrachlorodibenzodioxin (TCDD) is a known human carcinogen; however, its precise mechanism of action remains unclear. Here we show that TCDD induces mitochondrial dysfunction, stress signaling, and tumor invasion by a mechanism similar to that described for mtDNA-depleted cells. Treatment of C2C12 cells with TCDD disrupted mitochondrial transmembrane potential in a time-dependent fashion and inhibited mitochondrial transcription and translation. TCDD also increased cytosolic [Ca2+]c and RyR1-specific Ca2+ release. These changes were associated with increased calcineurin (CnA) levels and activation of CnA-sensitive NF-κB/Rel (IκBβ-dependent) factors. Cells treated with TCDD displayed resistance to apoptosis, increased expression of the tumor marker cathepsin L, and a high degree of invasiveness as tested by the Matrigel membrane invasion assay. These effects were reversed by the CnA inhibitor FK506, and CnA mRNA silencing suggesting that TCDD triggers a signaling pathway similar to mtDNA depletion. Taken together, these results reveal that TCDD may promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- January 2008
- DOI:
- 10.1073/pnas.0706183104
- Bibcode:
- 2008PNAS..105..186B
- Keywords:
-
- calcineurin;
- mitochondrial transcription;
- 2;
- 3;
- 7;
- 8-tetrachlorodibenzodioxin (TCDD);
- tumor invasion;
- transmembrane potential;
- Biological Sciences:Cell Biology