Many tumors overexpress members of the inhibitor of apoptosis protein (IAP) family. IAPs contribute to tumor cell apoptosis resistance by the inhibition of caspases, and are degraded by the proteasome to allow further progression of apoptosis. Here we show that tumor cells can alter the specificity of cytosolic proteolysis in order to acquire apoptosis resistance, which promotes formation of rapidly growing tumors. Survival of tumor cells with low proteasomal activity can occur in the presence of high expression of Tri-peptidyl-peptidase II (TPP II), a large subtilisin-like peptidase that complements proteasomal activity. We find that this state leaves tumor cells unable of effectively degrading IAPs, and that cells in this state form rapidly growing tumors in vivo. We also find, in studies of apoptosis resistant cells derived from large in vivo tumors, that these have acquired an altered peptidase activity, with up-regulation of TPP II activity and decreased proteasomal activity. Importantly, we find that growth of subcutaneous tumors is limited by maintenance of the apoptosis resistant phenotype. The apoptosis resistant phenotype was reversed by increased expression of Smac/DIABLO, an antagonist of IAP molecules. Our data suggest a reversible mechanism in regulation of apoptosis resistance that drives tumor progression in vivo. These data are relevant in relation to the multitude of therapy-resistant clinical tumors that have increased levels of IAP molecules.
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16 June 2003
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June 16 2003
Tumors Acquire Inhibitor of Apoptosis Protein (IAP)-mediated Apoptosis Resistance through Altered Specificity of Cytosolic Proteolysis
Xu Hong,
Xu Hong
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
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Lu Lei,
Lu Lei
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
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Rickard Glas
Rickard Glas
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
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Xu Hong
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
Lu Lei
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
Rickard Glas
1Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden
Address correspondence to Rickard Glas, Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital AB, 141 86 Stockholm, Sweden. Phone: 46-8-5858-9688; Fax: 46-8-746-7637; E-mail: [email protected]
*
Abbreviations used in this paper: IAP, inhibitor of apoptosis protein; NLVS, nitro-phenol-tri-leucine-vinyl-sulphone; TPP II, tri-peptidyl-peptidase II.
Received:
May 17 2002
Revision Received:
April 09 2003
Accepted:
April 23 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 197 (12): 1731–1743.
Article history
Received:
May 17 2002
Revision Received:
April 09 2003
Accepted:
April 23 2003
Citation
Xu Hong, Lu Lei, Rickard Glas; Tumors Acquire Inhibitor of Apoptosis Protein (IAP)-mediated Apoptosis Resistance through Altered Specificity of Cytosolic Proteolysis . J Exp Med 16 June 2003; 197 (12): 1731–1743. doi: https://doi.org/10.1084/jem.20020801
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