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)

Paclitaxel is a novel anticancer drug that has demonstrated efficacy toward treating several malignant tumor types. Here, we demonstrate that c-Jun NH(2)-terminal kinase (JNK), but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2, was persistently activated by paclitaxel or other microtubule-damaging agents within human leukemia HL-60 cells. Overexpression of a dominant-negative mutant, mitogen-activated protein kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide prevented paclitaxel-induced JNK activation, Bcl-2 phosphorylation and apoptosis. Furthermore, we found that the full-length MEKK1 was cleaved to a 91-kDa carboxyl-terminal fragment at the earlier time of apoptosis induced by microtubule-damaging agents. This cleavage, however, occurred consistently with JNK activation and Bcl-2 phosphorylation, but preceded DNA fragmentation in cells in response to paclitaxel activity. The caspase inhibitor Ac-Asp-Glu-Val-Asp-CHO (DEVD-CHO), but not Ac-Tyr-Val-Ala-Asp-CHO (Ac-YVAD-CHO), effectively blocked MEKK1 cleavage, JNK activation, Bcl-2 phosphorylation, and subsequent apoptosis. Subcellular fractionation revealed that the 91-kDa C-terminal MEKK1 fragment was translocated to cytosol. Notably, the MEKK1 fragment could be coimmunoprecipitated with anti-JNK antibodies, suggesting that a signaling complex of C-terminal MEKK1/stress-activated protein kinase/extracellular-signal regulated kinase 1/JNK formed during apoptosis induced by microtubule-damaging agents. Taken together, our results suggest that disruption of cytoarchitecture by paclitaxel triggers a novel apoptosis-signaling pathway, wherein an active DEVD-directed caspase (DEVDase) initially cleaves MEKK1to generate a proapoptotic kinase fragment that is able to activate JNK and subsequent Bcl-2 phosphorylation, finally eliciting cell death.
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PMID:Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells. 1116 Aug 61

Paclitaxel (PTX), a microtubule-active agent, blocks cell proliferation by inhibiting mitotic progression leading to mitotic and postmitotic arrest and cell death. Here we demonstrate for the first time that very low concentrations of PTX (3-6 nM) can completely inhibit cell proliferation without arresting cells at mitosis. At these low concentrations that are insufficient to inhibit mitotic progression, PTX induced both p53 and p21 causing G1 and G2 arrest in A549. In contrast, low PTX concentrations failed to induce G1 and G2 arrest in A549/E6 cells, that do not express p53. Furthermore, we observed that the levels of p53 and p21 induced by adriamycin and by low concentrations of PTX in A549 cells were comparable. This observation led us to conclude that low concentrations of PTX can induce p53 and p21 sufficiently to cause G1 and G2. Many other cell lines, including HCT116 cells, do not readily upregulate p53 in response to PTX, and therefore undergo exclusively mitotic and postmitotic arrest after PTX treatment. At low concentrations that do not cause mitotic arrest, PTX did not significantly inhibit proliferation of these cells. In HCT116 cells, loss of p53 (HCT/p53(-/-)) or p21 (HCT/p21(-/-)) affects both Bax and Bcl-2 expression. In cells lacking p53, levels of Bax and p21 were decreased. In cells lacking p21, levels of wt p53 were highly increased to compensate for the loss of p21. This in turn results in upregulation of Bax and downregulation of Bcl-2 resulting in an increase of the apoptotic Bax/Bcl2 ratio consistent with increased sensitivity of these cells to apoptotic stimuli. High levels of p53 and Bax/Bcl-2 ratio can also explain why loss of p21 is rarely found in human cancer.
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PMID:Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. 1143 44

A homology model for human Bcl-2 was built. Paclitaxel and baccatin III were individually docked into the Bcl-2 loop domain. The conformational space of the loop region on ligand binding was explored by molecular dynamics. The ligand-Bcl-2 interaction energy was calculated by minimization in the binding site. It was found that both paclitaxel's core skeleton and its C-13 side chain contribute significantly to its interaction with Bcl-2. A portion of the Bcl-2 loop domain was found to be locked by the bound paclitaxel and baccatin III in a similar conformation.
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PMID:A model for the interaction of paclitaxel with the Bcl-2 loop domain: a chemical approach to induce conformation-dependent phosphorylation. 1171 37

Anticancer agents induce cancer cell death through apoptosis or necrosis. As anticancer agents at low and high concentrations cause apoptosis and necrosis, respectively, cancer cells may be merely injured by an anticancer agent in apoptosis, and cell death may result from an activation of the internal constituents to induce apoptosis. Therefore, an alternation of apoptotic pathway must change the efficacy of anticancer agents. As an escape of cancer cells from apoptosis seems to be closely associated with the development of anticancer resistance, this report focuses on mechanisms of apoptosis and its association with anticancer resistance. A Bax induces apoptosis mitochondria-dependently, whereas Fas can induce apoptosis mitochondria-independently. An interaction of Bax and Bcl-2 is very important to decide cell life or death, and Bcl-2 phosphorylation may control this interaction: Paclitaxel treatment induced Bcl-2 phosphorylation and typical apoptosis, whereas hyperthermia induced not Bcl-2 phosphorylation but nuclear translocation and failed to induce apoptosis. Moreover, Fas was localized in the cytoplasm of exponentially growing cells and on the cell membrane of confluent cells. We would like to emphasize that it is very important to check the localization of constituents of apoptosis in order to evaluate the susceptibility of cancer cells to apoptosis.
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PMID:Apoptosis and anticancer drug resistance. 1177 40

Endothelin-1 (ET-1) is a powerful mitogenic peptide produced by different tumors. In ovarian carcinoma cells, ET-1 acts as an autocrine growth factor, selectively through ET(A) receptor (ET(A)R), which is predominantly expressed in tumor cells. The aim of this study was to examine whether ET-1 plays a role in the sensitivity of three ovarian carcinoma cell lines (OVCA 433, HEY, and SK-OV-3) to apoptosis induced by two different stimuli. Our results demonstrated that the addition of ET-1 markedly inhibited serum withdrawal and paclitaxel-induced apoptosis in a concentration-dependent manner, as demonstrated by Annexin-V assay, sub-G(1) peak in DNA content histograms, internucleosomal DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling method. Pretreatment of the cells with an ET(A)R antagonist, BQ 123, reversed the ET-1-induced protective effect. Paclitaxel-induced apoptosis resulted in the phosphorylation of Bcl-2 that was suppressed by the addition of ET-1. Further analysis of the signaling pathway demonstrated that ET-1 stimulated Akt activation. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin blocked ET-1-induced Akt phosphorylation. Inhibition of ET-1-stimulated mitogen-activated protein kinase activity did not affect ET-1 protection from paclitaxel-mediated apoptosis. Moreover, BQ 123 blocked the Akt-mediated pathway activated by ET-1, sensitizing ovarian carcinoma cells to paclitaxel treatment. These results establish a novel role for ET-1 in determining protection of ovarian carcinoma cells against paclitaxel-induced apoptosis through Bcl-2-dependent and PI3-K-mediated Akt pathways and suggest that ET-1 and ET(A)R could represent important targets for anticancer therapy.
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PMID:Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. 1185 32

Paclitaxel is able to cause cell death through the induction of apoptosis. Cell death characteristics for docetaxel have not yet been described in detail. We investigated four unselected human ovarian cancer cell lines for the sensitivity to a 1hr exposure to docetaxel and calculated the concentrations inhibiting 50% (IC(50)) and 90% (IC(90)) of cell growth. Of the cell lines A2780, H134, IGROV-1 (all wild-type p53) and OVCAR-3 (mutant, mt p53) A2780 was most sensitive and OVCAR-3 least sensitive. Equitoxic drug concentrations representing IC(90) values (25-510nM) were applied for 1hr to measure cell cycle distribution, DNA degradation, and to count apoptotic cell bodies and cells with multifragmented nuclei at various time-points after drug exposure. H134, IGROV-1 and OVCAR-3 showed a continued mitotic block up to at least 72hr and prolonged presence of cells with multifragmented nuclei. High percentages of apoptosis were calculated at 48hr and at later time-points. In contrast, A2780 cells accumulated in the S-phase of the cell cycle and apoptosis was hardly present. The changes in the expression levels of p53, p21/WAF1, Bax and Bcl-2, were not predictive for docetaxel-induced apoptosis. Caspase-3 activation occurred only in cells with accumulation in the G2/M phase starting as early as 8hr in OVCAR-3. Prolonged Bcl-2 phosphorylation was evident in OVCAR-3, visible at 24hr in H134 and IGROV-1, while this phenomenon did not occur in A2780. The mitogen-activated protein kinase pathway (JNKs/SAPKs or c-Jun N-terminal kinases/stress-activated protein kinases, JNK1/2; extracellular response kinase, ERK1/2; p38) did not seem to be directly involved in Bcl-2 phosphorylation or apoptosis. We conclude that docetaxel is able to activate caspase-3, induce Bcl-2 phosphorylation and apoptosis in cells that show a prolonged G2/M arrest, but cells may also die by a caspase-3-independent cell death mechanism.
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PMID:Variation in the kinetics of caspase-3 activation, Bcl-2 phosphorylation and apoptotic morphology in unselected human ovarian cancer cell lines as a response to docetaxel. 1199 42

Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose- and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria- and lysosome-rich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization.
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PMID:An association of Bcl-2 phosphorylation and Bax localization with their functions after hyperthermia and paclitaxel treatment. 1245 53

Microtubules are highly dynamic cellular polymers made of alphabeta-tubulin and associated proteins. They play a key role during mitosis, participating in the exact organization and function of the spindle, and are critical for assuring the integrity of the segregated DNA. Therefore, they represent one of the more effective targets in current cancer therapy. Paclitaxel (Taxol) is the prototype of the taxane family of antitumor drugs, and it was the first natural product shown to stabilize microtubules. This unique mechanism of action is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Taxanes block cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by subsequent multinucleated G1-like state related to mitotic slippage, depends on cell type and drug schedule. The development of fluorescent derivatives of paclitaxel led us to locate spindle pole microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids in living cells. In this review we discuss these findings in the context of a cell cycle-dependent response to taxanes, based on the cellular targets, and the status of the implicated cell cycle checkpoints. We also review those events that can influence this response, like the different signal transduction pathways activated/inactivated in relation to Bcl-2 phosphorylation and induction of apoptosis, and the controversial role of the p53 status on cell sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an emerging concept in combination sequential chemotherapy, is discussed on the basis of the cell cycle-dependent mechanisms of action of taxanes.
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PMID:Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. 1276 88

Paclitaxel has significant antitumor activity in several human tumors, including Kaposi's sarcoma (KS). Human herpesvirus 8 (HHV-8) is implicated in all forms of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), indicating that it is a DNA tumor virus. Since it is difficult to culture cell lines derived from KS patients, we used a cell line derived from PEL (BCBL-1) to investigate whether oxidative stress is involved in the cytotoxicity of paclitaxel on the HHV-8-related tumors. We found that the generation of reactive oxygen species (ROS) in the BCBL-1 cells was increased by paclitaxel treatment, and the increase in ROS production was suppressed by antioxidants, including catalase and ascorbic acid. Moreover, ascorbic acid also attenuated the cytotoxicity induced by paclitaxel. Upon paclitaxel treatment, caspase-2, caspase-3, and caspase-8 were activated in BCBL-1 cells. Cotreatment with antioxidants did not affect caspase-2, caspase-3 or caspase-8 activation. Paclitaxel-induced apoptosis was also accompanied by an increase in the protein levels of Bax, and this effect was attenuated by antioxidants. Paclitaxel slightly decreased the expression of Bcl-2 protein, but antioxidants induced Bcl-2 protein. These results suggest that oxidative stress is only partially involved in the cytotoxicity of paclitaxel in BCBL-1 cells, and that paclitaxel-induced apoptosis of BCBL-1 cells is primarily mediated by the caspase activation pathway.
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PMID:Involvement of oxidative stress and caspase activation in paclitaxel-induced apoptosis of primary effusion lymphoma cells. 1519 89

Paclitaxel and vincristine sulfate, two anti-microtubule agents are known to induce apoptosis. In this study, we tried to apprehend the relationship between the regulation of apoptotic proteins such as the Bcl-2-family proteins and the cytoskeleton structure during apoptosis induction by these two drugs. Paclitaxel and vincristine sulfate were used for a 24-h incubation and resulted in EC50 of 1 micro M and 1 micro g/ml, respectively. Under these conditions, paclitaxel treatment induced microtubule network polymerization, condensation of chromatin, characteristic features of early and late apoptosis as confirmed by orange acridine and ethydium bromide double staining. However, the shape of cells was not modified, while mitochondria changed their conformation from filamentous to aggregated corpuscles located around the nucleus. In addition, pro-apoptotic Bax protein remained in the cytoplasm, the beta-tubulin polymerization induced phosphorylation and inactivation of anti-apoptotic Bcl-2 and/or BclX/L proteins leading to intense mitochondria swelling and membrane disruption that are responsible for observed cytochrome c release and apoptotic proceeding. On the contrary, after vincristine sulfate treatment we observed morphological modifications such as cell shrinkage and nucleus condensation as the result of beta-tubulin depolarization and disruption of microtubules. Bax protein was intensively translocated into mitochondria membrane, decreasing the proportion of Bax/Bcl-2 or Bax/Bcl-xL heterodimers allowing the release of cytochrome c from the mitochondria and apoptotic process. In conclusion, our study demonstrated that the two anti-microtubule agents (paclitaxel and vincristine sulfate) induced apoptosis by two different pathways. However, mitochondrial dysfunction followed by cytochrome c release are the crucial events whatever the apoptotic signal, polymerization or disruption of beta-tubulin.
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PMID:Implication of bax in apoptosis depends on microtubule network mobility. 1525 27


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