Paclitaxel-mediated human aryl hydrocarbon receptor mRNA translation by an internal ribosomal entry site-dependent mechanism

Abstract

The aryl hydrocarbon receptor (AHR) is a ligandactivated transcription factor that is best known in mediating the toxicities of dioxins and dioxin-like compounds. AHR is activated by a variety of endogenous ligands and participating in tumor development. Thus, it will provide a new approach for cancer prevention and treatment to study the translation mechanism of AHR in tumor cells. In this study, we show that the 5'-untranslated region (UTR) of AHR mRNA contains an internal ribosome entry site (IRES). After mapping the entire AHR 5'-UTR, we determined that the full-length 5'-UTR is indispensable for the highest IRES activity. Interestingly, we found that AHR expression is induced in ovarian (A2780), breast (MDA-MB231), hepatic (Bel7402) and colorectal cancer cells (SW620) by chemotherapeutic drug paclitaxel (PTX) through IRES-dependent translation mechanism. Moreover, IRES activity is increased in the PTX-resistant ovarian cancer cells in which AHR protein expression was also enhanced. These results strongly suggest an important role for AHR IRES-dependent translation mechanism in cancer cell response to paclitaxel treatment.