Cell migration and metastasis markers as targets of environmental pollutants and the Aryl hydrocarbon receptor

Abstract

During the last few years, several studies have pointed to a surprising link between environmental pollutants cellular signaling and important cell functions such as plasticity, adhesion and migration. This unexpected link could be related to endogenous functions of pollutants receptors that may be disrupted by environmental factors, which is supported by observations in invertebrate species. It could also reveal novel toxic end-points and mechanisms of those pollutants, such as teratogenesis and cancer metastasis that are highly relevant from a public health point of view. In the present short article, we will review our recent observations on the aryl hydrocarbon receptor and its new molecular and cellular targets. We identified HEF1/NEDD9/CAS-L, a multifunctional protein involved in integrin-based signaling as a transcriptional target of the receptor, and showed that its induction was critical for cell plasticity mediated by environmental pollutants. We will put our studies in perspective with other observations made by several groups.

Figure 1

The AhR is a xenobiotic receptor, which forms a complex with chaperones in the cytoplasm. Upon ligand binding, it translocates to the nucleus and forms a transcription factor with its nuclear partner, ARNT. The heterodimer binds xenobiotic responsive elements (XRE) in the promoters of target genes. We identified HEF1/NEDD9/CAS-L as an AhR target. HEF1 induction is responsible for dioxin-mediated cell plasticity including E-Cadherin downregulation, JNK activation and increased cellular motility. Thus, HEF1 induction might be responsible of EMT (Epithelial Mesenchymal Transition)-associated processes. Other AhR-related regulatory pathways might be involved in those phenomena including regulation of Slug or TGFbeta signaling pathways.