期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 1, 页码 186-191出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0706183104
关键词
calcineurin; mitochondrial transcription; 2,3,7,8-tetrachlorodibenzodioxin (TCDD); tumor invasion; transmembrane potential
资金
- NCI NIH HHS [R01 CA022762, CA-22762, R37 CA022762] Funding Source: Medline
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-kappa B/Rel (I kappa B beta-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.
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