Carcinogenesis Advance Access published online on May 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl059
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1 INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus boulevard, Pointe-Claire, QC, Canada, H9R 1G6
* To whom correspondence should be addressed. Gap junctions mediate intercellular communication through channels composed of proteins, termed connexins (Cxs). We have shown that Cx32 is down-regulated in the liver of female rats exposed to hexachlorobenzene (HCB), an epigenetic environmental carcinogen. This is concomitant with the activation of the Integrin-linked kinase (ILK) pathway, leading to the activation and nuclear translocation of Akt and the inactivation of GSK3
Received January 28, 2006
Revised April 13, 2006
Accepted April 17, 2006
CARCINOGENESIS
Activation of the integrin-linked kinase pathway down-regulates hepatic Connexin32 via nuclear Akt
Isabelle Plante 1,
Michel Charbonneau 1,
and
Daniel G. Cyr 1 *
Daniel G. Cyr, E-mail: daniel.cyr{at}iaf.inrs.ca
Abstract 
. E-cadherin, an adhering junction protein, is also down-regulated in the liver of these female rats, due to the inactivation of GSK3. Using an in vitro model, the aim of this study was to determine the role of the ILK pathway in the regulation of Cx32. In order to mimic the activation of the ILK pathway, a well-differentiated rat hepatoma cell line, MH1C1, was transiently transfected with an expression vector for ILK (ILK+ cells). ILK+ cells displayed significantly lower Cx32 mRNA levels and Akt was also activated and translocated into the nucleus. Using a constitutively-active Akt expression vector, we showed that Akt transfected cells had lower Cx32 mRNA levels, indicating a role for Akt in Cx32 regulation. Finally, using an Akt-NES vector, a nuclear-active form of Akt, we showed that Cx32 protein levels were decreased in transfected cells as compared with cell transfected with the wild-type inactive Akt vector suggesting that that the nuclear form of Akt is responsible for the down-regulation of Cx32. Overall, these data indicate that Cx32 is down-regulated by the ILK pathway activation in rat hepatocytes and that this is mediated via the activation and nuclear translocation of Akt.
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