Carcinogenesis Advance Access originally published online on June 5, 2003
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Carcinogenesis, Vol. 24, No. 8, 1415-1423,
August 2003
© 2003 Oxford University Press
CARCINOGENESIS |
Aberrant Connexin 43 endocytosis by the carcinogen lindane involves activation of the ERK/mitogen-activated protein kinase pathway
1 INSERM EMI 00-09, IFR 50, Faculté de Médecine, Avenue de Valombrose, F-06107 Nice Cedex 02, France
2 INSERM U 364, IFR 50, F-06107 Nice Cedex 02, France
3 Université Paris 5, 45 rue des St Pères, F-75006 Paris, France
4 To whom correspondence should be addressed Email: mograbi{at}unice.fr
Although worldwide concerns have emerged about environmental factors that display carcinogenic and reprotoxic effects, little is known about the mechanism(s) by which these chemicals alter testicular function. Using the 42GPA9 Sertoli cell line, we recently reported that one widely used lipid-soluble pesticide, Lindane impairs gap junctional intercellular communication by promoting the intracellular localization of Connexin 43 (Cx43), a tumor suppressor. We showed here that this chemical triggered the accumulation of Cx43 within Rab5 positive endosomes. Interestingly, evidence is provided that Lindane-induced Cx43 endocytosis did not stem on alteration of Cx43 partition in lipid rafts. Lindane induced concomitantly Cx43 phosphorylation and activation of extracellular signal-regulated kinases (ERK) but not of JNK and p38 mitogen- activated protein kinases. Inhibition of ERK pathway by PD98059, a MEK1-specific inhibitor, prevented Lindane-induced Cx43 phosphorylation, restored Cx43 membranous localization and gap junction coupling. Altogether, these findings provide the first evidence that Lindane-altered Cx43 endocytosis requires ERK activation. Such inappropriate activation of the mitogenic MAPK pathway and inactivation of the tumor suppressor Cx43 by Lindane may participate in the promotion of neoplastic cell growth.
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