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

Abstract

Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

“…Our results reveal a differential response of primary immune cells and transformed cancer cells to AHR-mediated signals, which is in line with various toxicological studies using the classical exogenous AHR ligands TCDD and 3-methylcholanthrene 11,17,23 . Exposure to these xenobiotics leads to profound suppression of cellular and humoral immune responses 23 , while also promoting carcinogenesis and inducing tumour growth 11,17 . These cell-specific differences in AHR effects are likely to depend on the expression of factors differentially regulating AHR signal transduction such as the AHRR 20 as well as cell-specific transcription factor crosstalk shaping the response to AHR activation 24 .…”

“…AHR activation promotes clonogenicity and invasiveness of cancer cells 11,17 . Transgenic mice with a constitutively active AHR spontaneously develop tumours 18,19 , and the repressor of the AHR (AHRR) represents a tumour suppressor in multiple human cancers 20 .…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…To date, the clinical implications of AhR activation in the setting of CKD development and progression remain unclear, however, it has been postulated that uremic solutes might evoke dioxinlike toxicity, 38 leading to suppression of immune responses, induction of carcinogenesis and accelerating tumor growth, and promoting atherosclerosis. 38,98,99 It is well documented that several uremic toxins can induce apoptosis in a variety of cell types, such as smooth muscle cells, neutrophils, and proximal tubule cells. [100][101][102] However, only a few studies have reported a direct effect of uremic solutes on cell metabolism, including mitochondrial functioning.…”

The focal adhesion targeting domain of p130Cas confers a mechanosensing function

“…Contrasting with the primarily pro-migratory function ascribed to p130Cas (Tikhmyanova et al, 2010), NEDD9 function in cell migration is context specific; in some cell backgrounds, NEDD9 is pro-migratory (Ohashi et al, 1998;van Seventer et al, 2001;Kim et al, 2006;Natarajan et al, 2006;Bui et al, 2009;Izumchenko et al, 2009;Lucas et al, 2010;Kong et al, 2011), in others, NEDD9 restrains cell migration (Simpson et al, 2008;Seo et al, 2011;Zhong et al, 2012). This divergent function suggests that NEDD9 may tune the focal adhesion response depending on the tissue and cellular context.…”