Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells.
Exposure of rat liver epithelial cells to doxorubicin, an anthraquinone derivative widely employed in cancer chemotherapy, led to a dose-dependent decrease in gap junctional intercellular communication (GJC). Gap junctions are clusters of inter-cellular channels consisting of connexins, the major connexin in the cells used being connexin-43 (Cx43). Doxorubicin-induced loss of GJC was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated using inhibitors of ERK activation. Furthermore, activation of the epidermal growth factor (EGF) receptor by doxorubicin was responsible for ERK activation and the subsequent attenuation of GJC. Inhibition of GJC, however, was not by direct phosphorylation of Cx43 by ERK-1/2, whereas menadione, a 1,4-naphthoquinone derivative that was previously demonstrated to activate the same EGF receptor-dependent pathway as doxorubicin, resulting in downregulation of GJC, caused strong phos-phorylation of Cx43 at serines 279 and 282. Thus, ERK-dependent downregulation of GJC upon exposure to quinones may occur both by direct phosphorylation of Cx43 and in a phosphorylation-independent manner.
Abdelmohsen
Kotb
K
Institut für Biochemie und Molekularbiologie I, Heinrich-Heine-Universität Düsseldorf, D-40225 Düsseldorf, Germany.
von Montfort
Claudia
C
Stuhlmann
Dominik
D
Gerber
P Arne
PA
Decking
Ulrich K M
UK
Sies
Helmut
H
Klotz
Lars-Oliver
LO
D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D018031:Connexin 43 / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000502:physiology; D066246:ErbB Receptors / Q000187:drug effects* / Q000502:physiology; D017629:Gap Junctions / Q000502:physiology*; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344
D018031:Connexin 43; D008024:Ligands; D004317:Doxorubicin; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3