Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The combination of chemotherapy and radiation has been validated for the treatment of locally advanced non-small-cell lung cancer (NSCLC). However, the results are still unsatisfactory, and there is a need to improve current treatment. One approach is to use new agents that have the potential to enhance the efficacy of chemotherapy, radiation therapy (RT), or both. One potential target is the ubiquitin-proteasome pathway. This pathway plays an essential role in the degradation of most short- and long-lived intracellular proteins in eukaryotic cells and therefore regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib is a selective 26S proteasome inhibitor that has been approved for the treatment of multiple myeloma. Bortezomib has demonstrated in vitro chemotherapy- and RT-sensitizing properties as well as single-agent activity in lung cancer. This article will review the rationale for the use of bortezomib as part of the chemotherapy/RT strategy for the treatment of NSCLC.
Clin Lung Cancer 2005 Oct
PMID:The potential role of bortezomib in combination with chemotherapy and radiation in non-small-cell lung cancer. 1625 Sep 30

Small-cell lung cancer (SCLC) is a tobacco-related malignancy that usually presents in an extensive and therefore incurable stage. Although initially sensitive to platinum agent-based therapy, SCLC rapidly becomes refractory to chemotherapy, leading to disease recurrence and ultimately patient death. Treatment options following failure of first-line platinum agent-based therapy are limited. Small-cell lung cancer is characterized by molecular aberrancies such as overexpression of the antiapoptotic protein Bcl-2, which is regulated in part by the inhibitory IkappaB, a target of the ubiquitin-proteasome degradative pathway. Bortezomib is a proteasome inhibitor that can decrease Bcl-2 expression through diminished IkappaB degradation. Efforts to promote apoptosis in SCLC through the integration of bortezomib into therapy are under way.
Clin Lung Cancer 2005 Oct
PMID:Proteasome inhibition in small-cell lung cancer: preclinical rationale and clinical applications. 1625 Sep 31

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.
Lung Cancer 2005 Dec
PMID:Optimizing chemotherapy and targeted agent combinations in NSCLC. 1655 19

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.
Lung Cancer 2005 Dec
PMID:Optimizing chemotherapy and targeted agent combinations in NSCLC. 1655 71

MUT1 is an H-2Kb-restricted 8-mer CTL epitope expressed in Lewis lung carcinoma (3LL) tumor cells derived from C57BL/6 (B6) mice. We constructed a chimeric gene encoding ubiquitin-fused MUT1 (pUB-MUT1). By using a gene gun, B6 mice were immunized with the gene prior to challenge with 3LL tumor cells. Tumor growth and lung metastasis were prominently suppressed in mice immunized with pUB-MUT1 but only slightly in those immunized with the MUT1 gene (pMUT) alone. CD8+ T cells were confirmed to be the final effector by in vitro experiments and in vivo removal of the cells with a corresponding antibody. Anti-tumor immunity was profoundly suppressed in mice deficient in an immuno-subunit of proteasome, LMP7. Furthermore, mice deficient in a proteasome regulator, PA28alpha/beta, failed to acquire protective immunity. Thus, application of the ubiquitin-fusion degradation pathway was useful even in immunization with genes encoding a single CTL epitope for induction of specific and active CD8+ T cells.
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PMID:The ubiquitin-proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8+ T cells. 1656 81

The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2-p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21(waf1,cip1). These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.
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PMID:Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells. 1673 28

Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.
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PMID:Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. 1677 13

To clarify the involvement of autocrine motility factor (AMF) in the phenotype and biological profiles of human lung carcinomas, we analysed protein and mRNA expression in a total of 180 cases. Immunohistochemistry revealed positive staining in 67.2%, with the highest frequency in squamous cell carcinoma (SCC; 90.8%) and the lowest in small cell carcinoma (SmCC; 27.8%). In SCC, the staining frequency and intensity correlated with the degree of morphological differentiation. Generally, the expression levels in immunoblotting analysis corresponded well with immunohistochemical positivity. However, there was less agreement between protein and mRNA levels: in SmCC and large cell carcinomas (LCCs), mRNA showed higher, but protein showed lower expression. Among non-small cell lung carcinomas (NSCLCs), AMF protein levels correlated inversely with tumour size, but tumours exhibiting lymph node metastasis showed higher mRNA expression. In cultured lung carcinoma cells which comprised all histological subtypes, AMF was detected in the lysates of all ten cell lines. Secreted AMF protein was detected in the conditioned media from six cell lines, most of which were SmCC or LCC. Thus, a particular subset of lung carcinomas secrete AMF, which may promote cell motility via autocrine stimulation through its cognate receptor and cause the biological aggressiveness seen in SmCC and LCC. Moreover, treatment by proteasome inhibitors resulted in increased cellular AMF in five cell lines, suggesting that intracellular AMF levels are regulated by both secretion and proteasome-dependent degradation. In conclusion, AMF was detected in a major proportion of lung carcinomas, and may play a part not only in proliferation and/or progression of the tumours, but also, possibly, in the differentiation of SCC. Furthermore, higher mRNA expression may be related to the high metastatic potential of NSCLC and increased protein secretion, leading to a more aggressive phenotype, such as the invasiveness of SmCC and LCC.
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PMID:Differential expression and pathological significance of autocrine motility factor/glucose-6-phosphate isomerase expression in human lung carcinomas. 1702 20

Environmental carcinogen benzo(a)pyrene (BaP) generates electrophilic products BaP diolepoxide (BPDE) that react covalently with genomic DNA. Cells that acquire BaP/BPDE-induced DNA damage undergo S-phase arrest in a p53-independent manner. However, the role of Cdc25A in the BaP/BPDE-induced checkpoint is not clear. In the present study, we investigated the change of checkpoint kinase 1 (Chk1) and Cdc25A in S-phase arrest elicited by BaP. The results indicated that BaP (10microM, with S9 mixture) treatment induced S-phase arrest in both human lung carcinoma A549 cells and human bronchial epithelial cells line 16HBE cells, increasing the proportions of cells in S-phase 19.0% and 21.1%, respectively, at 12h after treatment, compared with DMSO control (p<0.01). Then, the S-phase arrest was weakened after 24h. The level of phorsphorylated Chk1 obviously increased and Cdc25A protein level decreased in both two cell lines after treatment with BaP. The results of RT-PCR indicate Cdc25A mRNA in both A549 cells and 16HBE cells was not changed after BaP treatment 12h, and 24h. The treatment of the proteasome inhibitor MG132 greatly increased Cdc25A protein in abundance. Over all, our results indicated Chk1-Cdc25A checkpoint pathway is involved in BaP-induced S-phase arrest. Moreover, transcription of Cdc25A did not change in BaP induced S-phase arrest, the decrease of Cdc25A level was due to increased degradation through the ubiqutin-proteasome pathway.
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PMID:The Cdc25A is involved in S-phase checkpoint induced by benzo(a)pyrene. 1760 18

Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in DNA damage response and telomere maintenance. Our previous report found that salvicine (SAL), a novel topoisomerase II poison, elicited DNA double-strand breaks and telomere erosion in separate experimental systems. However, it remains to be clarified whether they share a common response to these two events and in particular whether TRF2 is involved in this process. In this study, we found that SAL concurrently induced DNA double-strand breaks, telomeric DNA damage, and telomere erosion in lung carcinoma A549 cells. It was unexpected to find that SAL led to disruption of TRF2, independently of either its transcription or proteasome-mediated degradation. By overexpressing the full-length trf2 gene and transfecting TRF2 small interfering RNAs, we showed that TRF2 protein protected both telomeric and genomic DNA from the SAL-elicited events. It is noteworthy that although both the Ataxia-telangiectasia-mutated (ATM) and the ATM- and Rad3-related (ATR) kinases responded to the SAL-induced DNA damages, only ATR was essential for the telomere erosion. The study also showed that the activated ATR augmented the SAL-triggered TRF2 disruption, whereas TRF2 reduction in turn enhanced ATR function. All of these findings suggest the emerging significance of TRF2 protecting both telomeric DNA and genomic DNA on the one hand and reveal the mutual modulation between ATR and TRF2 in sensing DNA damage signaling during cancer development on the other hand.
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PMID:The telomeric protein TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA double-strand breaks driven by salvicine. 1802 71


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