The Inhibitory Mechanisms of the Tyrosine Kinase Inhibitors Herbimycin A, Genistein, and Tyrphostin B48 with Regard to the Function of the Aryl Hydrocarbon Receptor in Caco-2 Cells

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by dioxin and related xenobiotics. Although the activation of AhR is inhibited by tyrosine kinase inhibitors, the molecular mechanism has not been clarified. In the current study, the inhibitory mechanisms of several inhibitors of tyrosine kinase, herbimycin A, genistein, and tyrphostin B48, on AhR activation was analyzed in human Caco-2 cells. All the inhibitors suppressed the transcriptional activation of AhR induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Herbimycin A induced down-regulation of the AhR protein by inhibiting its molecular chaperone heat shock protein 90 (HSP90). In contrast, genistein and tyrphostin B48 inhibited the nuclear localization of AhR induced by TCDD, although the amount of AhR protein was not altered. The inhibitory effects of genistein and tyrphostin B48 on endogenous tyrosine kinase activity were evaluated by detection of alterations in the tyrosine phosphorylation states of cellular proteins.