Determining the role played by Aryl Hydrocarbon Receptor (AHR) in the colon carcinoma tumor model

Aryl hydrocarbon receptor (AHR), commonly known as an environmental sensor involved in the metabolism and elimination of xenobiotic substances, is also an important modulator in the development and functioning of the immune system. AHR expression is varied in the T cell subsets with the highest expression in T-helper 17 and T regulatory cells. Work from many researchers has suggested that AHR can act as a tumor promoter or a tumor suppressor depending on the tumor type. Our goal is to understand the role played by AHR in MC38 syngeneic colon carcinoma tumor model. In the absence of AHR, MC38 tumor progresses by an increase in tumor associated macrophages (TAMs), M2 macrophages and a decrease in CD8a positive cytotoxic lymphocytes. Analysis of the intratumoral cytokines reveals a pro-inflammatory phenotype. This has been assessed by pharmacologic blocking of the receptor using CH223191 and in AHR deficient (AHR-/-) mice. Therefore AHR acts as a tumor suppressor gene in colon carcinoma tumor model and silencing it may lead to colon cancer progression

LOOKING INTO THE ROLE PLAYED BY ARYL HYDROCARBON RECEPTOR (AHR) IN COLON CARCINOMA TUMOR MODEL

Aryl hydrocarbon receptor (AHR), commonly known as an environmental sensor involved in the metabolism and elimination of xenobiotic substances is also an important modulator in the development and functioning of the immune system. AHR expression is varied in the T cell subsets with the highest expression in T-helper 17 and T regulatory cell

p23 Modulates Aryl Hydrocarbon Receptor Protein Levels in Normal Cell Lines

Aryl hydrocarbon receptor (AHR) is a transcription factor activated in response to exposure of environmental toxins. Unliganded AHR resides in the cytosol of the cell bound to its chaperone protein complex contains two molecules of Hsp90, XAP2 and p23. Upon ligand binding, the receptor translocates to the nucleus and heterodimerizes with AHR nuclear translocator (ARNT) to activate its target genes expression. The effects of AHR activation have been primarily associated with numerous human diseases, especially cancers. As AHR is highly expressed in a panel of tumors, molecules that modulate AHR expression or antagonize aberrant AHR activity could be considered as potential candidates for the treatment of cancer

Down-Regulation of p23 in Normal Lung Epithelial Cells Reduces Toxicities From Exposure to Benzo[a]pyrene and Cigarette Smoke Condensate via an Aryl Hydrocarbon Receptor-Dependent Mechanism

The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which controls tumor growth and metastasis, T cell differentiation, and liver development. Expression levels of this receptor protein is sensitive to the cellular p23 protein levels in immortalized cancer cell lines. As little as 30% reduction of the p23 cellular content can suppress the AHR function. Here we reported that down-regulation of the p23 protein content in normal, untransformed human bronchial/tracheal epithelial cells to 48% of its content also suppresses the AHR protein levels to 54% of its content. This p23-mediated suppression of AHR is responsible for the suppression of (1) the ligand-dependent induction of the cyp1a1 gene transcription; (2) the benzo[a]pyrene- or cigarette smoke condensate-induced CYP1A1 enzyme activity, and (3) the benzo[a]pyrene and cigarette smoke condensate-mediated production of reactive oxygen species. Reduction of the p23 content does not alter expression of oxidative stress genes and production of PGE2. Down regulation of p23 suppresses the AHR protein levels in two other untransformed cell types, namely human breast MCF-10A and mouse immune regulatory Tr1 cells. Collectively, down-regulation of p23 suppresses the AHR protein levels in normal and untransformed cells and can in principle protect our lung epithelial cells from AHR-dependent oxidative damage caused by exposure to agents from environment and cigarette smoking