Konference: 2007 3. ročník Dny diagnostické, prediktivní a experimentální onkologie
Číslo abstraktu: 022p
Autoři: R. Vrzal; M. Daujat-Chavanieu; J. M. Pascussi; J. Ulrichová; P. Maurel; MUDr. Zdeněk Dvořák, Ph.D.
Perturbation of microtubular network has been shown to cause
suppression of inducibility of major cytochromes P450 (CYP) through
several nuclear receptors. Here we tested the effects of clinically
used microtubules-interfering agents (MIAs), such as colchicine,
vincristine, vinblastine and taxol on aryl hydrocarbon receptor
(AhR) signaling pathway in primary cultures of human hepatocytes.
We show that tested MIAs decreased induction of CYP1A2 mRNA by
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and restrict
TCDD-dependent nuclear translocation of AhR. On the other hand,
these MIAs increased the content of AhR protein and AhR mRNA by
transcriptional mechanism. We show that the MIAs activate
c-jun-N-terminal kinase (JNK), partly p38 but not
extracellular-regulated protein kinase (ERK). Consistently,
sorbitol, a model activator of JNK, inhibited TCDD-mediated
induction of CYP1A2 mRNA. We conclude that the effects of tested
MIAs on AhR-CYP1A2 signaling pathway are dual, i.e. they inhibit
transcriptional activity and nuclear translocation of AhR but in
parallel increase AhR protein and mRNA level. Microtubules
destabilizers have the same effects as stabilizer taxol. This
implies that AhR functions depend on microtubules dynamics but not
integrity. Perturbation of AhR-CYP1A2 signaling by MIAs comprises
AhR-JNK/p38 interactions. We also demonstrate that the effects of
MIAs in human hepatocytes do not proceed via arresting cell cycle
as confirmed by flow cytometry (FACS) analyses.
This work was supported by the grant from the Ministry of
Education, Youth and Sports of the Czech Republic MSM 6198959216
(to J.U.), by the grant from Grant Agency of the Czech Republic
GACR 303/07/0128 (to Z.D.) and by EMBO Short Term Fellowship ASTF
275-2006 (to Z. D.).
Datum přednesení příspěvku: 28. 11. 2007