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.
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.
Kasai
Shuya
S
Science of Bioresources, The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Japan.
Kikuchi
Hideaki
H
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D018938:Caco-2 Cells; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D017828:Rifabutin / Q000031:analogs & derivatives; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D018336:Receptors, Aryl Hydrocarbon; D020032:Tyrphostins; C107502:AG 494; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease