Cytosolic Ah Receptor: Mechanism of Action



 DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated receptor that has an unusual history. The AhR was initially identified as the intracellular protein that bound the environmental toxicant 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) with high affinity, and the receptor also bound structurally-related halogenated aromatics and polynuclear aromatic hydrocarbon combustion products. The toxic mechanisms induced by TCDD have been studied in depth and have not yet been completely resolved. The subsequent generation of the AhR knockout mouse models coupled with the discovery that this receptor binds a vast array of ligands including endogenous biochemicals, phytochemicals and pharmaceuticals have led to discoveries showing the important roles of the AhR in cellular homeostasis and multiple diseases including cancer. Thus, research on the AhR and its endogenous and exogenous ligands and mechanisms of action are essential for understanding the diverse functions of this receptor. The classical mechanisms of action of the AhR as a ligand-activated nuclear transcription factor are more complex and, in some cells, the AhR is active in both the nucleus and cytosol. Research in this laboratory has focused on the development and mechanisms of action of endogenous AhR ligands and AhR-active pharmaceuticals, and this application is focused on the proton pump inhibitor omeprazole which inhibits invasion of highly aggressive quasimesenchymal pancreatic ductal adenocarcinoma (QM- PDA) cell types. This AhR-dependent inhibitory effect in Panc1 cells (a QM-PDA cell line) occurs in the absence of ligand-induced nuclear uptake of the AhR or the induction of CYP1A1, a well-characterized biomarker of Ah-responsiveness. We hypothesize that a novel cytosolic AhR pathway mediates the inhibition of QM-PDA cell invasion by AhR-active pharmaceuticals and the mechanism of this response will be investigated in the following two Aims. Aim 1 will focus on the role of the cytosolic and nuclear AhR (AhRc and AhRn) in mediating the inhibition of cancer cell invasion and migration of QM-PDA and classical pancreatic cancer cell lines treated with omeprazole and other AhR-active pharmaceuticals. Aim2 will analyze the AhRc-mediated pathway in pancreatic cancer cells and determine the roles of nuclear import and export pathways/trafficking and potential cytosolic targets of the receptor. The proposed studies will determine a novel AhRc-mediated pathway in pancreatic cancer cells that could also be important for other functions of the receptor in different cell types.