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Tumors acquire inhibitor of apoptosis protein (IAP)-mediated apoptosis resistance through altered specificity of cytosolic proteolysis.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2003 Jun 16; Vol. 197 (12), pp. 1731-43. - Publication Year :
- 2003
-
Abstract
- 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.
- Subjects :
- Aminopeptidases
Animals
Antineoplastic Agents metabolism
Apoptosis Regulatory Proteins
Carrier Proteins metabolism
Cell Survival
Culture Media, Serum-Free
DNA Fragmentation
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Humans
Intracellular Signaling Peptides and Proteins
Mice
Mice, Inbred C57BL
Mitochondrial Proteins metabolism
Neoplasms, Experimental immunology
Nocodazole metabolism
Proteasome Endopeptidase Complex
Proteins immunology
Serine Endopeptidases genetics
Serine Endopeptidases metabolism
Tumor Cells, Cultured
Apoptosis
Cysteine Endopeptidases metabolism
Multienzyme Complexes metabolism
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1007
- Volume :
- 197
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 12810691
- Full Text :
- https://doi.org/10.1084/jem.20020801