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

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.

The Proteasome Is Required for Rapid Initiation of Death Receptor-Induced Apoptosis

“…Together with our observation that TNF did not induce degradation of XIAP as efficiently in HeLa H21 as in HeLa D98 cells, these results are in accordance with our hypothesis that the proteasome is required for an efficient initiation of the death program. In further support of our assumption are also recent findings demonstrating, in vitro and in vivo, that tumors acquired apoptosis resistance by down regulating their proteasomal activity (14,22). As the proteolytic activity is essential for every proliferating cell, these tumors adapted to the low proteasomal activity by switching to another newly identified proteolytic system, the tripeptidyl peptidase II (15).…”

“…As the proteolytic activity is essential for every proliferating cell, these tumors adapted to the low proteasomal activity by switching to another newly identified proteolytic system, the tripeptidyl peptidase II (15). Due to the hereby altered specificity of cytosolic proteolysis, however, these tumors were unable to efficiently degrade the various IAPs, including XIAP, resulting in rapidly growing tumors in vivo (22).…”

Mitotic Infidelity and Centrosome Duplication Errors in Cells Overexpressing Tripeptidyl-Peptidase II

“…Treatment with an inhibitor of TPP II induced apoptosis in BL and BL-like cells suggesting that the enzyme may control processes that are intimately associated with the growth and survival of this tumor. A similar involvement of TPP II in the regulation of tumor cell growth was recently suggested by the finding that up-regulation of TPP II in proteasome inhibitors adapted EL4 cells correlated with enhanced tumorigenicity in vivo and with up-regulation of members of the IAP family of antiapoptotic proteins (15).…”

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…During the apoptosis, the mitochondrial Smac/DIABLO inhibits the inhibitors of apoptosis proteins (IAP), thereby breaking the brake on apoptosis. For further information, we accredit the reader to the review articles [10,11] The internal death stimulators "mitochondrial pathway":…”