Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism

Abstract

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 cellcell 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.

Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity

“…The contribution of AhR to this regulation was assessed using two different approaches; first, we treated the MDA-MB-231 mammary cells, which do not express AhR, with dioxin (see Supplementary information SF3). We did not observe Hef1 mRNA induction as observed with AhR-expressing HepG2 and MCF-7 cells (Diry et al, 2006). Next, we performed AhR mRNA knockdown with our validated siRNAs (Qiagen, Courtaboeuf, France) (see also Figures 1c and d).…”

“…Thus, alternative mechanisms have been investigated (Mulero-Navarro et al, 2005;Diry et al, 2006). The activation of this receptor has been shown to elicit diverse cellular alterations, including modifications of cell cycle regulation, cell migration and contact inhibition (Mulero-Navarro et al, 2005;Puga et al, 2005;Diry et al, 2006). These alterations could possibly mediate part of the long-term toxicities of the AhR ligands in animals and humans; chronic exposure to several AhR ligands, which are common and persistent pollutants, is frequent in industrialized populations (tobacco smoke, air pollution, food contamination).…”

“…However, this function accounts for only part of the toxicity of AhR ligands, as shown by targeted knockouts of some of the CYP genes. Thus, alternative mechanisms have been investigated (Mulero-Navarro et al, 2005;Diry et al, 2006). The activation of this receptor has been shown to elicit diverse cellular alterations, including modifications of cell cycle regulation, cell migration and contact inhibition (Mulero-Navarro et al, 2005;Puga et al, 2005;Diry et al, 2006).…”

“…We have investigated the possible implication of AhR in those events as any dysregulation of these cellular pathways may disrupt normal fetal development and favor cancer progression in addition to a variety of other toxic effects. We have particularly focused on regulatory proteins that control cellular migration; indeed, preliminary large-scale studies indicated that the Nedd9/ Hef1/Cas-L gene (named Hef1 in the rest of the article) might be modulated by dioxin in human cultured cells (Frueh et al, 2001;Diry et al, 2006).…”

A remarkable new target gene for the dioxin receptor

“…Mechanistically, such effects on morphology and migration involved reduced expression of the cellcell interaction protein E-Cadherin and activation of the c-Jun N-terminal kinase (JNK) pathway. 35 In following studies, the same laboratory has further defined the signaling involved in the modulation of adhesion and migration by dioxin. They found that dioxin induces the expression of a member of the Cas family of proteins, Nedd9/Hef1/CasL, 36 which has …”