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Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D
Author(s) -
Van Der Stappen Jos W. J.,
Williams Ann C.,
Maciewicz Rose A.,
Paraskeva Christos
Publication year - 1996
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19960807)67:4<547::aid-ijc14>3.0.co;2-4
Subject(s) - cathepsin b , cell culture , cathepsin c , cathepsin , cancer research , adenoma , secretion , cathepsin d , biology , adenocarcinoma , microbiology and biotechnology , cancer , chemistry , endocrinology , enzyme , biochemistry , genetics
The aim of our study was to identify changes in secreted procathepsin B levels in a model of the human colorectal adenoma to carcinoma sequence and to determine the factors required for its extracellular activation. Conversion of the non‐tumorigenic adenoma‐derived cell line PC/AA to a highly tumorigenic phenotype (designated AA/C1/SB10/M) was associated with an 8‐fold increase in the presence of the proform of cathepsin B in 24 hr conditioned serum‐free medium (SFM). In addition, mature enzyme was only detected in the cell lines of this model with increased malignant potential. This is in agreement with the findings of a previous study, in which mature cathepsin B was only present in the 24 hr conditioned SFM of cancer‐derived cell lines and not in SFM from adenoma‐derived cell lines. Having demonstrated a reduction in the pH of conditioned medium from cell lines with increased malignant potential, we used a range of specific proteinase inhibitors to show that an aspartyl proteinase was involved in the initial activation of procathepsin B. Consistent with this finding, we subsequently demonstrated an increased secretion of the aspartyl proteinase cathepsin D in the medium of the AA/C1/SB10/M adenocarcinoma cells compared with the non‐tumorigenic AA/C1 cell line. Therefore, the presence of mature cathepsin B in the conditioned medium of the more malignant cell lines coincided with a reduction in pH and an increase in the amount of cathepsin D secreted. Data from the human colorectal derived adenoma to carcinoma sequence indicate that an in vivo mechanism may exist that, dependent on the simultaneous presence of both a tumour‐generated acidic extracellular environment and an elevated secretion of procathepsin D, could result in the activation of latent procathepsin outside the cell. © 1996 Wiley‐Liss, Inc.