Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway

• Published in: Chemical research in toxicology Vol. 28; no. 5; pp. 907 - 918
• Main Authors: Jin, Un-Ho, Kim, Sang-Bae, Safe, Stephen
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18.05.2015
• Subjects: Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cytochrome P-450 CYP1A1 - metabolism; Female; Humans; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - prevention & control; Omeprazole - pharmacology; Pancreas - drug effects; Pancreas - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction - drug effects
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx5005198

Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonists that inhibit the invasion of breast cancer cells through inhibition of CXCR4 transcription. Treatment of highly invasive Panc1 pancreatic cancer cells with TCDD, omeprazole, and seven other AhR-active pharmaceuticals showed that only omeprazole and tranilast, but not TCDD, inhibited invasion in a Boyden chamber assay. Similar results were observed in MiaPaCa2 cells, another quasimensenchymal pancreatic ductal adenocarcinoma (QM-PDA) pancreatic cancer cell line, whereas invasion was not observed with BxPC3 or L3.6pL cells, which are classified as classical (less invasive) pancreatic cancer cells. It was also observed in QM-PDA cells that TCDD, omeprazole, and tranilast did not induce CYP1A1 or CXCR4 and that treatment with these compounds did not result in nuclear uptake of AhR. In contrast, treatment of BxPC3 and L3.6pL cells with these AhR ligands resulted in induction of CYP1A1 (by TCDD) and nuclear uptake of AhR, which was similar to that observed for Ah-responsive MDA-MB-468 breast and HepG2 liver cancer cell lines. Results of AhR and AhR nuclear translocator (Arnt) knockdown experiments in Panc1 and MiaPaCa2 cells demonstrated that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt-independent. These results demonstrate that in the most highly invasive subtype of pancreatic cancer cells (QM-PDA) the selective AhR modulators omeprazole and tranilast inhibit invasion through a nongenomic AhR pathway.