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

Abstract

Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonist that inhibit invasion of breast cancer cell 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 in BxPC3 or L3.6pL cells which are classified as “classical” (less invasive) pancreatic cancer cells. It was also observed that in the QM-PDA cells that TCDD, omeprazole and tranilast did not induce CYP1A1 or CXCR4 and treatment with these compounds did not result in nuclear uptake of the 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 the 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 demonstrate that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt-independent. These results demonstrate that in the most highly invasive sub-type of pancreatic cancer cells (QM-PDA), the selective AhR modulators omeprazole and tranilast inhibit invasion through a non-genomic AhR pathway.

The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy

“…Differential AhR expression has been observed in tumor vs. normal tissues for multiple tumors, and the levels and prognostic significance of the AhR are tumor-specific [26–37]. For example, a recent survey of tumor array database showed that AhR mRNA expression in breast, lung, prostate and cervical cancers was similar to non-tumor tissue, whereas expression was higher in stomach, thyroid, colon and pancreatic tumors compared to non-tumor tissue [34]. Moreover, high expression of the AhR in pancreatic tumors was a prognostic factor for increased patient survival [34].…”

“…For example, a recent survey of tumor array database showed that AhR mRNA expression in breast, lung, prostate and cervical cancers was similar to non-tumor tissue, whereas expression was higher in stomach, thyroid, colon and pancreatic tumors compared to non-tumor tissue [34]. Moreover, high expression of the AhR in pancreatic tumors was a prognostic factor for increased patient survival [34]. In contrast, high expression of the nuclear AhR was a negative prognostic factor for urothelial cancer patients [30].…”

“…In ER-negative MDA-MD-231 cells, TCDD and omeprazole, but not 4-hydroxytamoxifen, flutamide, leflunomide, mexiletine, nimodipine, sulindac and tranilast, inhibited migration and this was due, in part, to AhR-dependent downregulation of the pro-migration gene CXCR4 [43]. We also carried out a similar migration inhibition study in pancreatic cancer cells and among the pharmaceuticals, only omeprazole and tranilast (but not TCDD) were active and mechanistic studies showed that this inhibitory response was CXCR4-independent and due to a non-genomic pathway [34]. The effects of omeprazole as an inhibitor of breast and pancreatic cancer cell invasion and metastasis in vivo and in vitro suggest that benzimidazole analogs of omeprazole may be useful scaffolds for developing AhR mediated anticancer agents, and these studies are currently in progress.…”

Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma

“…In this case, internalization of CXCR4 does not occur. Instead, the receptor is inhibited at the transcriptional level [52]. Because of this, the results of ongoing clinical trials evaluating the effects of CQ and HCQ will play a pivotal role in the validation or withdrawal of preclinical findings.…”

Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases?

“…Additionally, and in contrast to concerns about carcinogenicity, several of these drugs have been shown to suppress the growth, invasion, and/or metastases of experimental cancers in an AhR dependent manner [37–41]. Taken together, these findings provide further evidence that TCDD should not set the precedent for the selective discrimination against the development of RMAhRLs.…”