Plante, Isabelle 
ORCID: https://orcid.org/0000-0003-2080-6450; Cyr, Daniel G. ORCID: https://orcid.org/0000-0002-6566-783X et Charbonneau, Michel
(2005).
Involvement of the integrin-linked Kinase pathway in hexachlorobenzene-induced gender-specific rat hepatocarcinogenesis
Toxicological Sciences
, vol. 88
, nº 2.
pp. 346-357.
DOI: 10.1093/toxsci/kfi323.
Résumé
Overexpression of the integrin-linked kinase (ILK) pathway disrupts cell-cell interactions, an epigenetic event leading to epithelial cell transformation. Female rats exposed to hexachlorobenzene (HCB) for 5 consecutive days and sampled 45 days later show a decrease in liver gap junctional intercellular communication. We hypothesized that HCB also alters E-cadherin expression and that this alteration is mediated by the ILK pathway. Hepatic ILK levels were markedly increased in HCB-treated female rats. Cytoplasmic/membrane levels of protein kinase B (Akt), a target of ILK, and its phosphorylated active form were decreased in treated female rats. Flow cytometric analysis showed a concomitant increase in nuclear Akt levels. Both ILK and Akt can phosphorylate glycogen synthetase kinase-3beta (GSK3beta), rendering it inactive. Phosphorylated-GSK3beta levels were higher in treated females and resulted in a twofold decrease in the activity of GSK3beta. The inactivation of GSK3beta in HCB-treated female rats resulted in the nuclear translocation of beta-catenin, as demonstrated by both immunocytochemistry and flow cytometric analyses. Western blot analysis showed an 84% decrease in E-cadherin levels in HCB-treated rats as compared to controls, and this decrease was not mediated by Snail activation. Mimicking the activation of ILK with specific GSK3beta inhibitors resulted in downregulation of E-cadherin levels but had no effect on Cx32 expression in the MH(1)C(1) cells. Overall, these results indicate that hepatic E-cadherin is downregulated as a result of an overexpression of the ILK pathway. The concomitant HCB-induced downregulation of intercellular communication does not occur as a result of either E-cadherin downregulation or GSK3beta inactivation.
| Type de document: | Article |
|---|---|
| Mots-clés libres: | Carcinogenesis; junction; E-cadherin; β-catenin; glycogen synthetase kinase-3β; connexins |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 11 nov. 2024 20:36 |
| Dernière modification: | 11 nov. 2024 20:36 |
| URI: | https://espace.inrs.ca/id/eprint/15070 |
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