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Journal of Biochemistry Advance Access originally published online on December 14, 2006
Journal of Biochemistry 2007 141(2):287-292; 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

*To whom Correspondence should be addressed. Tel: +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 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 ß1 integrin receptor and some ß1 integrin-dependent signalling 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-{kappa}B. The data suggest that CPT induces inhibition of collagen biosynthesis in cultured human skin fibroblasts by stimulation of NF-{kappa}B signalling.

Key Words: camptothecin, collagen metabolism, integrin signalling, prolidase

Abbreviations: BCIP/NBT, 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium liquid substrate reagent; CPT, camptothecin; DMEM, Dulbecco's minimal essential medium; EDTA, ethylenediaminetetraacetic acid; ERK1 and ERK2, extracellular-signal-regulated kinase 1 and kinase 2; FAK, non-receptor focal adhesion kinase pp125FAK; FBS, fetal bovine serum; Grb2, growth-factor receptor-bound protein 2; MAPK, mitogen activated protein kinases; MEK, mitogen/extracellular signal regulated kinase; NF-{kappa}B, nuclear transcription factor {kappa}B; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; Raf, protein kinase signaling proteins; Ras, GTP-binding protein; SDS, sodium dodecylsulfate; Shc, Src, non-receptor tyrosine kinases signaling proteins; Sos, son of sevenless protein; TBS-T, Tris buffered saline with Tween 20


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