Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteasome inhibitors can resensitize cells that are resistant to tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly(ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated resensitization of TRAIL.
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PMID:Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. 1608 82

This review synthesizes recent insights on the signaling pathways triggered by glucocorticoids during apoptosis of thymocytes. Thymocyte apoptosis is a complex process, which is involved in thymic selection. Even if the main partners are identified, there still remain dark zones on the whole pathway and notably on the crosstalk between each signaling cascade. Glucocorticoids trigger thymocyte apoptosis by enhancing cyclin-dependent kinase 2 activity, downregulating the expression of antiapoptotic Bcl-2 proteins, and upregulating that of proapoptotic Bcl-2 proteins. These events result in mitochondrial alterations and subsequent caspase activation. Proteasome intervenes at various levels of the signaling cascades--for instance, degrading the glucocorticoid receptor or caspase inhibitory proteins. Changes in intracellular K+ and Ca2+ concentrations are involved in caspase and endonulease activation. All these effects are dependent on macromolecular synthesis. The only known non-genomic effect of glucocorticoids is an early production of sphingolipids (ceramide and sphingosine), which are involved in caspase activation independent of mitochondrial alterations. Externalization of phosphatidylserine, a process mediating phagocytosis of dying thymocytes, depends on pathways that diverge from those leading to nuclear apoptosis.
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PMID:Signaling pathways involved in glucocorticoid-induced apoptosis of thymocytes. 1616 81

Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-kappaB) activation. Because stimulated HSCs also trigger NF-kappaB activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-kappaB activation and, more importantly, NF-kappaB inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-kappaB target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.
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PMID:Proteasome inhibition induces hepatic stellate cell apoptosis. 1644 Mar 46

Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level.
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PMID:Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells. 1647 41

Human neutrophils underwent spontaneous apoptosis, which was accompanied by degradation of Mcl-1, but not other anti-apoptotic molecules (cIAP1, cIAP2, A1, survivin and Bcl-2). Spontaneous neutrophil apoptosis and Mcl-1 degradation were prevented by cyclic AMP (cAMP) agonists (dibutyryl cAMP and prostaglandin E(1)), and the effects of cAMP agonists on neutrophils were highly resistant to cycloheximide, a protein synthesis inhibitor, although slight increase in Mcl-1 mRNA expression was induced by cAMP agonists. Proteasome inhibitors (epoxomicin and lactacystin) also prevented spontaneous neutrophil apoptosis and Mcl-1 degradation to the same extent as cAMP agonists, and no additive effect was obtained by combination of cAMP agonists and proteasome inhibitors. These findings suggest that cAMP agonists, like proteasome inhibitors, delay neutrophil apoptosis primarily via stabilization of Mcl-1.
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PMID:Cyclic AMP delays neutrophil apoptosis via stabilization of Mcl-1. 1687 95

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1alpha (SDF-1alpha), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIM(EL) by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasome-mediated degradation. However, SDF-1alpha and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIM(EL) degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIM(EL) phosphorylation through the ERK pathway targets the protein for proteasomal degradation.
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PMID:Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. 1715 1

Proteasome inhibitors are a novel class of compounds that might increase sensitivity to chemotherapy for acute myeloid leukemia (AML). We quantified apoptosis in THP-1 cells incubated with idarubicin (IDA) alone or together with a low concentration of MG132 or bortezomib. The combination of both drugs yielded a percentage of apoptotic cells that was significantly higher than the additive effect of both drugs administered separately (p < 0.01). Isobologram analysis showed that both MG132 and bortezomib interacted synergistically with IDA to induce apoptosis of THP1 cells. Western blot analysis of Bax and Bim show an acumulation of these pro-apoptotic proteins in THP1 treated cells. This increase in Bim preceded the induction of apoptosis and participated in idarubicin-induced apoptosis. Proteasome inhibition also potentiated IDA-induced apoptosis in primary blast cells from 22 AML patients while no such effect was found on normal lymphocytes, PHA-stimulated lymphocytes, normal cord blood CD34+ cells or bone marrow normal myeloid cells. These data show that MG132 and bortezomib specifically sensitize leukemic cells to IDA through an increase in BIM and Bax pro-apoptotic Bcl-2 family proteins.
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PMID:Proteasome inhibition specifically sensitizes leukemic cells to anthracyclin-induced apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins. 1737 88

Proteasome inhibitors exhibit antitumoral activity against malignancies of different histology. Emerging evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, thus it seems plausible that activation of survival signaling cascades might compromise their antitumoral effects. Bcl-2-associated athanogene (BAG) family proteins are characterized by their property of interaction with a variety of partners involved in modulating the proliferation/death balance, including heat shock proteins (HSP), Bcl-2, Raf-1. In this report, we demonstrated that BAG3 is a novel antiapoptotic molecule induced by proteasome inhibitors in various cancer cells at the transcriptional level. Moreover, we demonstrated that BAG3 knockdown by siRNA sensitized cancer cells to MG132-induced apoptosis. Taken together, our results suggest that BAG3 induction might represents as an unwanted molecular consequence of utilizing proteasome inhibitors to combat tumors.
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PMID:Transcriptional upregulation of BAG3 upon proteasome inhibition. 1799 94

Proteasome inhibitors display potent anti-neoplastic and anti-angiogenic properties both in vitro and in vivo. The mechanisms, however, by which proteasome inhibitors kill tumor cells are still fairly elusive as is the molecular basis of resistance to treatment. To address these questions, we employed a high-throughput Western blotting procedure to analyze changes in a subproteome of approximately 800 proteins in the promyelocytic leukemia cell line HL-60 upon treatment with the proteasome inhibitor PSI (Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde) and correlated the changes of selected target proteins with the changes in two multidrug-resistant HL-60 variants. In total, 105 proteins were upregulated more than 1.5-fold after PSI treatment, while 79 proteins were downregulated. Activation of caspases-3 and -8, modulation of members of the Bcl-2 family as well as stimulation of stress signaling pathways was prominent during HL-60 apoptosis. We also identified changes in the abundance of proteins previously not known to be affected by proteasome inhibitors. In contrast, two multidrug-resistant HL-60 cell lines, overexpressing either MRP1 or P-glycoprotein were largely resistant to PSI-induced apoptosis and could not be resensitized by the pharmacological inhibitors of the drug efflux pumps MK571 or PSC833. Drug resistance was also independent of the upregulation of Bad. Overexpression of multidrug resistance proteins, P-glycoprotein and MRP-1 is thus not sufficient to explain resistance of HL-60 cells to treatment with proteasome inhibitor PSI, which remains more closely related to a low level of Bax expression and to the inability to activate JNK. Alternative routes to the acquisition of resistance to PSI have therefore to be considered.
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PMID:Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI. 1846 79

Malignant pleural mesothelioma (MPM) is an aggressive malignancy tightly associated with asbestos exposure. The increasing incidence of MPM and its resistance to all therapeutic modalities necessitate an urgent development of new treatments for MPM. Proteasome inhibitors (PIs) have emerged as promising agents for treating human cancers that are refractory to current chemotherapies. In this study, we characterized MG132, a commonly used PI, for its proapoptotic and anti-invasion activities in NCI-H2452 and NCI-H2052 human thoracic MPM cell lines to determine the therapeutic effect of PIs on MPM. We found that as low as 0.5 microM MG132 caused a significant apoptosis in both cell lines as evidenced by DNA damage, cleavage of poly ADP-ribose polymerase and caspases 3, 7, and 9, and mitochondrial release of Smac/DIABLO and Cytochrome c. Mitochondrial caspase activation was found to be the underlying mechanism of the MG132-induced apoptosis. Mcl-1, among the Bcl-2 and IAP (inhibitor of apoptosis protein) antiapoptotic family proteins tested, was proved to be a major inhibitor of the MG132-induced apoptosis in MPM cells. Meanwhile, subapoptotic doses of MG132 inhibited the invasion of both MPM cell lines through reducing Rac1 activity. These observations demonstrate that MG132 possesses proapoptotic and anti-invasion activities in human MPM cells, therefore encouraging further investigations on the value of PIs for treating MPM.
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PMID:Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells. 1879 23


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