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J. Biol. Chem., Vol. 276, Issue 33, 30686-30693, August 17, 2001
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From the Proprotein convertases (PCs) of the
subtilisin/kexin family are responsible for the activation of
prohormones, protrophic factors, and their receptors. We sought to
determine whether loss of PC-mediated activities might affect the
malignant phenotypes of cancer cells. Stable transfectants of
Inhibition of Proprotein Convertases Is Associated with Loss of
Growth and Tumorigenicity of HT-29 Human Colon Carcinoma Cells
IMPORTANCE OF INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) RECEPTOR
PROCESSING IN IGF-1-MEDIATED FUNCTIONS*
§,,,
,**
Laboratory of Biochemical
Neuroendocrinology, Clinical Research Institute of Montreal, Montreal,
Quebec H2W 1R7, Canada, the ¶ Laboratoire de Biochimie Cellulaire,
CNRS UPRESA 6032, Faculté de Pharmacie, Marseille Cedex 5, 13385, France, the Molecular Medicine and Disease of Aging
Center, Loeb Health Research Institute, Ottawa Civic Hospital, Ottawa,
Ontario K1Y 4K9, Canada, and the § Departments of Surgery
and Medicine, McGill University, and the Royal Victoria Hospital,
Montreal, Quebec H3A 1A1, Canada
1-antitrypsin Portland (1-PDX)
cDNA, coding for a potent PC inhibitor, were analyzed in model
HT-29 cells (HT-29/PDX) and in other cell lines. Expression of
1-PDX resulted in a proinsulin-like growth factor-1
receptor (pro-IGF-1R) processing blockade, hence inhibiting the ability of exogenous IGF-1 to induce tyrosine phosphorylation of its
-subunit and insulin-related substrate-1. Coexpression of IGF-1R
with four different PCs or the novel convertase SKI-1 in the
furin-defective LoVo-C5 cells demonstrated that pro-IGF-1R (~200 kDa)
cleavage into IGF-1R (-subunit, ~105 kDa) can be achieved by furin
and PC5A, but not by PACE4, PC7, or SKI-1. Expression of
1-PDX resulted in reduction of DNA synthesis and in
anchorage-independent growth. Following serum deprivation, the
1-PDX transfectants exhibited an enhanced apoptotic
phenotype and were insensitive to IGF-1-mediated [3H]thymidine incorporation and protection against
apoptosis. These cells showed reduced invasiveness that paralleled
decreased mRNA levels of urokinase-type plasminogen activator and
its receptor, tissue-type plasminogen activator, and plasminogen
activator inhibitor-1. Comparative subcutaneous inoculation of cells in
nude mice revealed that animals injected with HT-29/PDX cells exhibited
delayed and lower incidence of tumor development as well as reduced
tumor size. Immunohistochemical analysis of CD31 antigen expression, a
marker of endothelial cells, revealed reduced HT-29/PDX tumor vascularization. These findings indicate that PCs actively contribute to the growth and malignant phenotypes of HT-29 tumors, suggesting that
PC inhibition strategies may be a useful adduct to the arsenal of
colorectal anticancer gene therapies.
*
This work was supported by Canadian Institutes of Health
Research (CIHR) Group Grant MGC-11474 and by the Protein Engineering Network of Centres of Excellence Program supported by the Government of
Canada.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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