Involvement of the integrin-linked kinase pathway in hexachlorobenzene-induced gender-specific rat hepatocarcinogenesis.
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.
Plante
Isabelle
I
INRS-Institut Armand-Frappier, Université du Québec, Pointe-Claire, Canada.
Cyr
Daniel G
DG
Charbonneau
Michel
M
D000284:Administration, Oral; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D017630:Connexins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006581:Hexachlorobenzene / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D051176:beta Catenin / Q000378:metabolism; D000097002:Gap Junction beta-1 Protein; D000099200:Scaffold Protein ILK
D015820:Cadherins; D002273:Carcinogens; D017630:Connexins; D005659:Fungicides, Industrial; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006581:Hexachlorobenzene; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; D000097002:Gap Junction beta-1 Protein; D000099200:Scaffold Protein ILK; C000605508:Gsk3b protein, rat