Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism.
Environmental chemicals such as dioxin adversely affect immune, neurological and reproductive functions and have been implicated in cancer development. However, the mechanisms responsible for dioxin toxicity are still poorly understood. Here, we show that dioxin and related pollutants trigger a marked morphological change in epithelial cells that remodel their cytoskeleton to increase interaction with extra cellular matrix while loosening cell-cell contacts. Furthermore, dioxin-treated cells show increased motility. These dioxin-mediated effects are mimicked by constitutive expression and activation of the intracellular dioxin receptor (aryl hydrocarbon receptor (AhR)). They correlate with activation of the Jun NH2-terminal kinase (JNK) and are reverted by treatment with a JNK inhibitor. Dioxin-induced effects occur 48 h post-treatment initiation, a time scale, which argues for a genomic effect of the AhR, linked to induction of target genes. This novel Ahr action on cell plasticity points to a role in cancer progression.
Diry
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M
UMR-S 490 INSERM, UFR Biomédicale des Saints Pères, Paris, Cedex, France.
Tomkiewicz
C
C
Koehle
C
C
Coumoul
X
X
Bock
K Walter
KW
Barouki
R
R
Transy
C
C
D000199:Actins / Q000378:metabolism; D001551:Benz(a)Anthracenes / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008024:Ligands; D008748:Methylcholanthrene / Q000378:metabolism / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism* / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke; D014026:Nicotiana
D000199:Actins; D001551:Benz(a)Anthracenes; D015820:Cadherins; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D012906:Smoke; C053714:cholanthrene; D008748:Methylcholanthrene; D048031:JNK Mitogen-Activated Protein Kinases