Prolidase-independent mechanism of camptothecin-induced inhibition of collagen biosynthesis in cultured human skin fibroblasts.
The present study was undertaken to evaluate the mechanism of campthotecin (CPT)-induced deregulation of collagen metabolism in cultured human skin fibroblast. It has been found that CPT strongly induced inhibition of collagen biosynthesis. The mechanism of this phenomenon was found to be independent of prolidase activity, an enzyme that plays an important role in enhancement of collagen biosynthesis at post-translational level. In fact, the enzyme activity was found to be stimulated by CPT. Increase in the enzyme activity was accompanied by increase in the expression of beta(1) integrin receptor and some beta(1) integrin-dependent signalling proteins, Sos, MAPK (ERK(1), ERK(2)) and transcription factor NF-kappaB. Since activation of beta(1) integrin induces NF-kappaB that inhibits collagen gene transcription, therefore the mechanism of CPT-dependent inhibition of collagen biosynthesis may be related to beta(1) integrin-dependent stimulation of NF-kappaB. Supporting evidence comes from experiments showing that specific MEK/ERK inhibitor (UO126) inhibited CPT-induced up-regulation of prolidase activity while it had no effect on CPT-induced inhibition of collagen biosynthesis and activation of NF-kappaB. The data suggest that CPT induces inhibition of collagen biosynthesis in cultured human skin fibroblasts by stimulation of NF-kappaB signalling.
Miltyk
Wojciech
W
Department of Medicinal Chemistry, Medical University in Bialystok, Kilińskiego 1, 15-089 Bialystok, Poland.
Karna
Ewa
E
Palka
Jerzy A
JA
D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004150:Dipeptidases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012867:Skin / Q000166:cytology; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism
D019012:Integrin beta1; D016328:NF-kappa B; D020839:Son of Sevenless Protein, Drosophila; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases; D004150:Dipeptidases; C022449:proline dipeptidase; D002166:Camptothecin