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ToxSci Advance Access published online on September 14, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi323
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 28, 2005
Accepted September 9, 2005

Carcinogenicity

Involvement of the Integrin-Linked Kinase Pathway in Hexachlorobenzene-Induced Gender-Specific Rat Hepatocarcinogenesis

Isabelle Plante 1, Daniel G. Cyr 1*, and Michel Charbonneau 1

1 INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus boulevard, Pointe-Claire, QC, Canada, H9R 1G6

* To whom correspondence should be addressed.
Daniel G. Cyr, E-mail: daniel.cyr{at}iaf.inrs.ca


  Abstract

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 five 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 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 females. Flow cytometric analysis showed a concomitant increase in nuclear Akt levels. Both ILK and Akt can phosphorylate glycogen synthetase kinase-3{beta} (GSK3{beta}), rendering it inactive. Phosphorylated-GSK3{beta} levels were higher in treated females and resulted in a two-fold decrease in the activity of GSK3{beta}. The inactivation of GSK3{beta} 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 GSK3{beta} inhibitors resulted in down-regulation of E-cadherin levels, but had no effect on Cx32 expression in the MH1C1 cells. Overall, these results indicate that hepatic E-cadherin is down-regulated as a result of an overexpression of the ILK pathway. The concomitant HCB-induced down-regulation of intercellular communication does not occur as a result of either E-cadherin down-regulation or GSK3{beta} inactivation.

Keywords: Carcinogenesis; Junction; E-cadherin; {beta}-catenin; Glycogen synthetase kinase-3{beta}; Connexins.
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