Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-mediated immunity is effective against cells harboring active virus replication, and is critical for the elimination of ongoing infections, regression of virus-associated tumors, and reducing or preventing the reactivation of persistent viruses. The capacity of persistent and oncogenic viruses to maintain a long-term relationship with their host presupposes viral mechanisms for circumventing antiviral defenses. By suppressing the expression of molecules associated with antigen processing and presentation, viruses abrogate the major immune mechanism that deals with the elimination of infected and tumor cells. This is accomplished either by transcriptional downregulation of genes encoding class I MHC antigens, peptide transporter molecules, and the proteasome-associated LMP subunits, or by interfering with transport of class I molecules to the cell surface. In some cases viruses shut off the expression of most viral proteins during latency or express mainly nonimmunogenic or antagonistic peptide epitopes. This review describes selective mechanisms utilized by viruses for interference with antigen processing and presentation, and addresses their significance for in vivo viral persistence and tumor progression.
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PMID:Selective mechanisms utilized by persistent and oncogenic viruses to interfere with antigen processing and presentation. 853 Aug 79

Cell-mediated immunity is effective against cells harboring active virus replication and is critical for the elimination of ongoing infections, opposing tumor progression, and reducing or preventing the reactivation of persistent viruses and tumor metastasis. The capacity of persistent viruses and tumor cells to maintain a long-term relationship with their host presupposes mechanisms for circumventing antiviral or antitumor defenses. By suppressing the expression of molecules associated with antigen processing and presentation, abrogation of the major immune mechanism that deals with the elimination of infected and transformed cells is achieved. This is accomplished in tumors predominantly by transcriptional downregulation of genes encoding class I major histocompatibility complex antigens, peptide transporter molecules, and the proteasome-associated low molecular mass protease subunits, and in cells expressing viral proteins by interfering with peptide transport and the assembly/transport of class I complexes. In addition, virus-infected cells and selected tumor cells express mainly nonimmunogenic or antagonistic peptide epitopes. This review describes mechanisms used by viruses and in transformed cells for interference with antigen processing and presentation and addresses their significance for in vivo viral persistence and tumor progression.
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PMID:Modulation of antigen processing and presentation by persistent virus infections and in tumors. 929 29

The c-myc proto-oncogene encodes a short-lived transcription factor that plays an important role in cell cycle regulation, differentiation and apoptosis. c-myc is often rearranged in tumors resulting in deregulated expression. In addition, mutations in the coding region of c-myc are frequently found in human lymphomas, a hot spot being the Thr58 phosphorylation site, a mutation shown to enhance the transforming capacity of c-Myc. It is, however, still unclear in what way this mutation affects c-Myc activity. Our results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that abolish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over at normal rates in these cells. Myc Thr58 mutants expressed ectopically in other cell types also exhibit reduced proteasome-mediated degradation, which correlates with a substantial decrease in their ubiquitination. These results suggest that ubiquitin/proteasome-mediated degradation of c-Myc is triggered by Thr58 phosphorylation revealing a new important level of control of c-Myc activity. Mutation of Thr58 in lymphoma thus escapes this regulation resulting in accumulation of c-Myc protein, likely as part of the tumor progression. (Blood. 2000;95:2104-2110)
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PMID:c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. 1070 81

The degradation of most eukaryotic cells is controlled by the ubiquitin proteasome pathway. This pathway is responsible not only for the degradation of short and long-lived proteins but also tumor suppressors, transcription factors and cell cycle proteins. Altered degradation of these proteins is thought to promote cancer growth and spread. By contrast, inhibition of the proteasome would lead to cell cycle arrest and ultimately programmed cell death, or apoptosis. A structured review of the published literature examining the role of ubiquitin proteasome inhibition in cancer growth and regulation is provided. Advances in the development of proteasome inhibitors have allowed detailed investigation of this pathway in cancer growth. Relevant in vitro and in vivo studies of proteasome inhibition as pertains to cancer therapy are detailed. The ubiquitin proteasome pathway is critical in the degradation of proteins involved in cell cycle control and tumor growth. Proteasome inhibitors have been shown to arrest or retard cancer progression, by interfering with the ordered, temporal degradation of regulatory molecules. Clinical trials examining the agents have begun.
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PMID:Ubiquitin proteasome pathway: implications and advances in cancer therapy. 1171 28

Functional inactivation of the tumor suppressor protein p53 by accelerated ubiquitin/proteasome-dependent proteolysis is a common event in tumor progression. Proteasomal degradation is inhibited by the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen-1, which acts as a transferable element on a variety of proteasomal substrates. We demonstrate that p53 chimeras containing GAr domains of different lengths and positions within the protein are protected from proteolysis induced by the ubiquitin ligases murine double minute 2 and E6-associated protein but are still ubiquitinated and retain the capacity to interact with the S5a ubiquitin-binding subunit of the proteasome. The GAr chimeras transactivate p53 target genes, induce cell cycle arrest and apoptosis, and exhibit improved growth inhibitory activity in tumor cells with impaired endogenous p53 activity.
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PMID:Functional p53 chimeras containing the Epstein-Barr virus Gly-Ala repeat are protected from Mdm2- and HPV-E6-induced proteolysis. 1180 82

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation and the loss of responsiveness to TGF-beta may contribute to the development of human cancers. In hepatocellular carcinomas, the potential role of TGF-beta signaling as a tumor suppressor pathway can be illustrated by the presence of mutations in genes encoding TGF-beta receptors or downstream components of this signaling such as Smad2. Although Smad2 is mutated in hepatocellular carcinomas, the alteration of TGF-beta signaling with respect to tumor progression remains to be established. Using the HepG2 hepatoma cells, we showed here that expression of Smad2.Q407R, a missense mutation found in human hepatocellular carcinoma, was less effective than expression of wild-type Smad2 in enhancing the ability of TGF-beta to induce transcription from the Mix.2 promoter. This effect was specifically associated with a decrease in the steady-state level of Smad2.Q407R, presumably because of an enhancement of its ubiquitination and degradation through the proteasome machinery. More importantly, we found that the unstability of Smad2.Q407R was reversed when this mutant undergoes homo-oligomerization with wild-type Smad2 or hetero-oligomerization with Smad3 within the cells. Therefore, our findings allowed us to propose a novel mechanism for suppression of the deleterious effect of a tumor-derived mutation of Smad2, which loss may lead to dysregulated cell proliferation during tumorigenesis.
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PMID:Evidence for a role of Smad3 and Smad2 in stabilization of the tumor-derived mutant Smad2.Q407R. 1270 Feb 38

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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PMID:Tumors acquire inhibitor of apoptosis protein (IAP)-mediated apoptosis resistance through altered specificity of cytosolic proteolysis. 1281 Jun 91

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. 1286 67

PS-341 (bortezomib) represents a new class of therapeutics that targets the ubiquitin-proteasome pathway. It has broad-spectrum single-agent anticancer activity and can potentiate chemotherapy and radiation in preclinical models. Early phase clinical studies have shown tolerability and activity in multiple myeloma, lymphoma, prostate cancer, and lung cancers. By its mechanism of inhibiting protein degradation, PS-341 targets a wide range of pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27(Kip1), p53, nuclear factor-kappaB, Bcl-2, and Bax. PS-341 is currently in phase I/II clinical development in both non-small cell lung cancer and small cell lung cancer. This article will review the preclinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Proteasome inhibition with PS-341 (bortezomib) in lung cancer therapy. 1498 79

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
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PMID:Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. 1498 53


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