Biswas Gopa, Srinivasan Satish, Anandatheerthavarada Hindupur K, Avadhani Narayan G
Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):186-91. doi: 10.1073/pnas.0706183104. Epub 2008 Jan 2.
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 Ca(2+) and RyR1-specific Ca(2+) release. These changes were associated with increased calcineurin (CnA) levels and activation of CnA-sensitive NF-kappaB/Rel (IkappaBbeta-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.
环境毒素2,3,7,8-四氯二苯并二恶英（TCDD）是一种已知的人类致癌物；然而，其确切作用机制仍不清楚。在此我们表明，TCDD通过一种类似于针对线粒体DNA缺失细胞所描述的机制诱导线粒体功能障碍、应激信号传导和肿瘤侵袭。用TCDD处理C2C12细胞以时间依赖性方式破坏线粒体跨膜电位，并抑制线粒体转录和翻译。TCDD还增加了胞质[Ca(2+)]c和RyR1特异性Ca(2+)释放。这些变化与钙调神经磷酸酶（CnA）水平升高和CnA敏感的NF-κB/Rel（IkappaBbeta依赖性）因子的激活有关。用TCDD处理的细胞表现出对凋亡的抗性、肿瘤标志物组织蛋白酶L的表达增加以及通过基质胶膜侵袭试验测试的高度侵袭性。这些效应被CnA抑制剂FK506和CnA mRNA沉默所逆转，表明TCDD触发了类似于线粒体DNA缺失的信号通路。综上所述，这些结果揭示TCDD可能通过直接靶向线粒体转录和诱导线粒体应激信号传导在体内促进肿瘤进展。
