Latency of cathepsin B secreted by human colon carcinoma cells is not linked to secretion of cystacin C and is relieved by neutrophil elastase |
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Authors: | Daniel Keppler Patrice Waridel Magnus Abrahamson Daniel Bachmann José Berdoz Bernard Sordat |
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Institution: | 1. Experimental Pathology Unit, Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges s. Lausanne, Switzerland;2. Department of Clinical Chemistry, University Hospital, University of Lund, S-221 85 Lund, Sweden |
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Abstract: | The lysosomal cystein proteinase cathepsin B is shown to be secreted by ten human colon carcinoma cell lines and to accumulate in culture media as a latent enzyme. The cell lines also secrete a physiological inhibitor of cathepsin B, cystatin C. A significant correlation was found between secretion of the latent enzyme and the inhibitor (r = 0.755, P < 0.01). The aim of the present study was to modulate the respective secretion of the two antagonists to test whether or not latency of cathepsin B was due to the concomitant secretion of the inhibitor. SW480 colon carcinoma cells were treated with the acidotropic agent ammonium chloride, phorbol 12-myristate 13-acetate, and the inflammatory cytokines TGF-β, TNF-α, and IL-1β. Ammonium chloride significantly increased latent cathepsin B levels without affecting the constitutive secretion of cystatin C. Phorbol 12-myristate 13-acetate induced a 4- to 5-fold increase in secreted latent cathepsin B, but did not alter significantly the accumulation of cystatin C in media. The cytokines, TGF-β, TNF-α, and IL-1β, had no major effect on the expression of these two antagonists. Latent cathepsin B released from human carcinoma cells could be efficiently activated by neutrophil elastate at neutral pH. It is concluded that latent cathepsin B is a true proenzyme rather than an enzyme-inhibitor comples. In addition, our data from neutrophil elastate activation experiments indicate that a proteolytic system for activation of the tumor cell-secreted latent enzyme may exist in vivo. |
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Keywords: | cathepsin B cystatin C tumor invasion neutrophil elastase colon E-64 L-3-carboxytrans-2 3-epoxypropyl-leucylamido-(4-guanidino) butane DMEM Dulbecco's modified Eagle's minimum essential medium FCS fetal call serum DTT 1 4-dithio-D L-threitol EDTA ethylenediamine tetracetic acid disodium salt |
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