The Journal of Experimental Medicine
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Published 16 June 2003. doi:10.1084/jem.20020801
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© Rockefeller University Press, 0022-1007/2003/6/1731 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1731-1743

Tumors Acquire Inhibitor of Apoptosis Protein (IAP)-mediated Apoptosis Resistance through Altered Specificity of Cytosolic Proteolysis

Xu Hong1,2, Lu Lei1,2 and Rickard Glas1,2

1 Microbiology and Tumor Biology Center (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
2 Center 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: rickard.glas{at}mtc.ki.se

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.

Key Words: apoptosis • proteasome • tri-peptidyl-peptidase II • IAP • caspase


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