Cyclic AMP inhibits TGFbeta1-induced cell-scattering and invasiveness in murine-transformed keratinocytes.
Mouse-transformed keratinocytes cultured in the presence of transforming growth factor beta1 (TGF-beta1) acquire an array of morphologic and functional properties that give rise to a migratory phenotype that expresses mesenchymal molecular markers. This cellular conversion involves activation of the Ras-ERK pathway, enhancement of urokinase (uPA) and matrix metalloproteinase-9 (MMP-9) expression and induction of invasiveness. In our present work, we demonstrate that cAMP and forskolin are able to prevent the expression of these mesenchymal properties, probably due to blockade of the Ras-ERK pathway. Our results also show that cAMP and forskolin are able to abolish the TGF-beta1-induced reorganization of the actin cytoskeleton that is characteristic of the mesenchymal phenotype and also inhibits the disruption of the E-cadherin cell to cell interactions. The latter responses seem to depend on the activity of protein kinase A, as demonstrated by the activation of the Ras-ERK pathway by specific protein kinase A inhibitors.
Santibáñez
Juan F
JF
Laboratorio de Biología Celular INTA, Universidad de Chile, Santiago, Chile. jfsantib@uec.inta.uchile.cl
Olivares
Daniela
D
Guerrero
Javier
J
Martínez
Jorge
J
D000818:Animals; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005576:Colforsin; D000242:Cyclic AMP; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one