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Journal of Biochemistry Advance Access published online on December 14, 2006
Journal of Biochemistry, doi:10.1093/jb/mvm022
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© 2006 The Japanese Biochemical Society

Prolidase - independent mechanism of camptothecin - induced inhibition of collagen biosynthesis in cultured human skin fibroblasts.

Wojciech Miltyk, Ewa Karna and Jerzy A Palka*

Department of Medicinal Chemistry, Medical University in Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland, phone: (48) (85) 748-5706, fax: (48) (85) 879-5703, e-mail: pal{at}amb.edu.pl

*Correspondence address: Jerzy A. Palka, Ph.D., Department of Medicinal Chemistry, Medical University in Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland. Phone: (48) (85) 748-5706; fax: (48) (85) 879-5703; e-mail: pal{at}amb.edu.pl

Received November 23, 2006; Accepted December 11, 2006


  Abstract

The present study was undertaken to evaluate the mechanism of 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 ß1 integrin receptor and some ß1 integrin-dependent signaling proteins, Sos, MAPK (ERK1, ERK2) and transcription factor NF-{kappa}B. Since activation of ß1 integrin induces NF-{kappa}B that inhibits collagen gene transcription, therefore the mechanism of CPT-dependent inhibition of collagen biosynthesis may be related to ß1 integrin-dependent stimulation of NF-{kappa}B. 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-kB. The data suggest that CPT induces inhibition of collagen biosynthesis in cultured human skin fibroblasts by stimulation of NF-{kappa}B signaling.

Key Words: Camptothecin, Collagen metabolism, integrin signaling, Prolidase


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