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)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity. TRAIL is known to induce apoptosis in cancer cells but spare most normal cells. In this study, we examined whether treatment of docetaxel (DTX) can enhance apoptotic cell death by TRAIL against androgen-independent prostate cancer (AIPC). The cell death effect of combinations of TRAIL and docetaxel on prostate cancer cell lines (androgen-dependent LNCaP and its derived androgen-independent, metastatic C4-2B) was evaluated by synergisms of apoptosis. Western blot assay and DNA fragmentation assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL induced apoptosis in the presence of docetaxel. In addition, we investigated the in vitro anti-tumor effects of combined docetaxel and TRAIL using MAP kinase inhibitors. Docetaxel itself could not induce apoptotic cell death in 24 h even in high concentration. Apoptotic cell death, however, was drastically enhanced by pretreatment of docetaxel 20 h before TRAIL treatment. Docetaxel enhanced the PARP-1 cleavage and caspases activation by TRAIL especially in androgen-independent, metastatic C4-2B cell line, mainly by phosphorylation of Bcl-2 by JNK activation. It appears that apoptotic cell death was protected by the JNK inhibitor SP600125. The results of our study show that pretreatment of docetaxel is able to enhance the apoptosis produced by TRAIL in prostate cancer cells, especially in hormone-refractory prostate cancer (HRPC).
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PMID:Pretreatment of docetaxel enhances TRAIL-mediated apoptosis in prostate cancer cells. 1840 75

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce mitochondrial apoptotic signaling that can be negatively regulated by prosurvival Bcl-2 proteins. ABT-737 is a small-molecule BH3 mimetic that binds to and antagonizes Bcl-2/Bcl-x(L) but not Mcl-1. We show that ABT-737 can synergistically enhance TRAIL-mediated cytotoxicity in human pancreatic cancer cell lines. ABT-737 was shown to enhance TRAIL-induced apoptosis as shown by DNA fragmentation, activation of caspase-8 and Bid, and cleavage of caspase-3 and poly(ADP-ribose) polymerase. A Bax conformational change induced by TRAIL was enhanced by ABT-737. ABT-737 disrupted the interaction of Bak with Bcl-x(L) in both cell lines. Furthermore, ABT-737 untethered the proapoptotic BH3-only protein Bim from its sequestration by Bcl-x(L) or Bcl-2. Bim small hairpin RNA (shRNA) was shown to attenuate caspase-3 cleavage and to reduce the cytotoxic effects of TRAIL plus ABT-737 compared with shRNA control cells. Finally, Mcl-1 shRNA potentiated caspase-3 cleavage by ABT-737 and enhanced its cytotoxic effects. Taken together, ABT-737 augments TRAIL-induced cell killing by unsequestering Bim and Bak and enhancing a Bax conformational change induced by TRAIL. These findings suggest a novel strategy to enhance cross-talk between the extrinsic and intrinsic apoptotic pathways to improve therapeutic efficacy against pancreatic cancer.
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PMID:BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. 1841 64

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent due to its selectivity in killing transformed cells. However, TRAIL can also stimulate the proliferation and metastasis of TRAIL-resistant cancer cells. Thus, acquired TRAIL resistance during TRAIL therapy would shift the patient's treatment from beneficial to detrimental. In this study, we focused on the acquired TRAIL resistance mechanism and showed that the elevated expression of the antiapoptotic factor cellular FLICE-like inhibitory protein (c-FLIP) and the prosurvival Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) underlie the main mechanism of this type of TRAIL resistance in lung cancer cells. Chronic exposure to TRAIL resulted in lung cancer cell resistance to TRAIL-induced cytotoxicity, and this resistance was associated with the increase in the cellular levels of c-FLIP(L) and Mcl-1(L). Overexpresssion of c-FLIP(L) suppressed recruitment of caspase-8 to the death-inducing signaling complex, whereas increased Mcl-1(L) expression blunted the mitochondrial apoptosis pathway. The elevation of c-FLIP(L) and Mcl-1(L) expression was due to Akt-mediated stabilization of these proteins in TRAIL-resistant cells. Importantly, suppressing c-FLIP(L) and Mcl-1(L) expression by RNA interference collectively alleviated acquired TRAIL resistance. Taken together, these results identify c-FLIP(L) and Mcl-1(L) as the major determinants of acquired TRAIL resistance and could be molecular targets for improving the therapeutic value of TRAIL against lung cancer.
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PMID:Akt-mediated eminent expression of c-FLIP and Mcl-1 confers acquired resistance to TRAIL-induced cytotoxicity to lung cancer cells. 1848 3

Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-alpha (TNF-alpha), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1(-/- )mice. Circulating TNF-alpha levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1(-/-) animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1(-/-) mice.DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-alpha.
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PMID:Infliximab and etanercept are equally effective in reducing enterocyte APOPTOSIS in experimental colitis. 1864 6

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has been shown to induce apoptosis in cancer cells but not normal cells. TRAIL triggers apoptosis through binding to its receptors DR4 and KILLER/DR5. Chemo or radiotherapy induces apoptosis through activation of p53 in response to cellular damage, whereas TRAIL induces apoptosis independent of p53. Mutations or deletions of p53 occurred in more than half of human tumors confer resistance to chemo-radiotherapy. Treatment of TRAIL-resistant tumors with agents targeting death receptors, intrinsic Bcl-2 family members, inhibitor of apoptosis proteins or PI3K/Akt pathway restores the sensitivity to TRAIL-induced apoptosis. Combination of rhTRAIL or the agonist antibody for TRAIL receptor with conventional chemotherapeutic agents results in enhanced efficacy in preventing tumor progression and metastasis. Therefore, the rational design of TRAIL-based therapy combining with other modality that either synergizes to apoptosis induction or overcomes the resistance represents a challenging strategy to achieve the systemic tumor targeting and augment the antitumor activity of cancer therapeutics.
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PMID:The promise of cancer therapeutics targeting the TNF-related apoptosis-inducing ligand and TRAIL receptor pathway. 1893 88

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agnostic antibodies, which are being evaluated clinically as anticancer therapies, selectively kill cancer cells through the death receptors DR4 and DR5. However, their therapeutic potential is limited by occurring resistance in tumor cells. Here, we compared the apoptotic response of a panel of six human breast cancer cell lines with recombinant human TRAIL and antibodies to DR4 or DR5. Despite their total mRNA and protein expression, TRAIL death receptors, with a higher frequency in DR4, are absent on cell surface in some cell lines. Loss of cell surface expression of DR4 or DR5 accounts for resistance to their corresponding antibody and, importantly, correlates with a decreased sensitivity to TRAIL. TRAIL resistance occurs when both receptors are absent on cell surface regardless of alterations in Bcl-2 family proteins or caspases. Furthermore, inhibition of endocytosis by pharmacologic inhibitors or disruption of clathrin-dependent endocytosis signaling components (adaptor protein 2 and clathrin) restores cell surface expression of the death receptors and sensitize TRAIL-resistant cells to TRAIL-induced apoptosis. DR4 endocytosis appears to be mediated by its cytoplasmic domain EAQC(337)LL. The results show that TRAIL death receptors undergo constitutive endocytosis in some breast cancer cells. Loss of cell surface expression of DR4 and DR5 could be evaluated as a biomarker for TRAIL resistance in breast tumors. Moreover, the clathrin-mediated endocytosis pathway could be a potential target for therapeutics to overcome tumor resistance to TRAIL receptor-targeted therapies.
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PMID:TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. 1907 31

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that has an important role in immunity and inflammation by inducing cellular responses such as apoptosis. The transcription factor nuclear factor-kappaB (NF-kappaB) can paradoxically suppress and promote apoptosis in response to TNF-alpha. In this study, we found that p53 upregulated modulator of apoptosis (PUMA), a p53 downstream target and a BH3-only Bcl-2 family member, is directly regulated by NF-kappaB in response to TNF-alpha. TNF-alpha treatment led to increases in PUMA mRNA and protein levels in human colon cancer cells. The induction of PUMA was p53 independent, and mediated by the p65 component of NF-kappaB through a kappaB site in the PUMA promoter. The apoptotic effect of PUMA induction by TNF-alpha was unmasked by depleting the antiapoptotic protein Bcl-X(L). In mice, PUMA was also induced by TNF-alpha in an NF-kappaB-dependent manner. TNF-alpha-induced apoptosis in a variety of tissues and cell types, including small intestinal epithelial cells, hepatocytes, and thymocytes, was markedly reduced in PUMA-deficient mice. Collectively, these results demonstrated that PUMA is a direct target of NF-kappaB and mediates TNF-alpha-induced apoptosis in vitro and in vivo.
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PMID:PUMA is directly activated by NF-kappaB and contributes to TNF-alpha-induced apoptosis. 1944 83

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently being investigated as a therapeutic agent for a variety of malignancies, as it triggers apoptosis specifically in transformed cells. However, TRAIL use as a stand alone therapeutic is hampered by the fact that many primary tumor cells are resistant to TRAIL-mediated apoptosis. Here, we investigated the extent to which pretreatment of TRAIL-resistant primary B-cell chronic lymphocytic leukemia (B-CLL) cells with histone deacetylase inhibitors (HDACis) could render them susceptible to killing by TRAIL. We found that HDAC inhibition in B-CLL cells led to increased TRAIL receptor expression, increased caspase activation, decreased expression of antiapoptotic regulators such as Bcl-2, and ultimately, enhanced TRAIL-induced apoptosis. Importantly, untransformed peripheral blood mononuclear cells remained largely resistant to TRAIL, even in the presence of HDACis. These results suggest that combination therapies using HDAC inhibition and TRAIL could prove beneficial for the treatment of B-CLL.
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PMID:[Not Available]. 1954 14

Tumor necrosis factor (TNF) participates in regulation of many processes including carcinogenesis and apoptosis. However, at present, there are practically absent the works on peculiarities of regulation of apoptosis in tnf-knockout (tnf-/-) mice. These mice develop without morphological abnormalities, but they seem to have disturbances of many biological processes, such as inflammation, programmed cell death, etc. Therefore, the goal of our work was to study possible pathways of regulation of apoptosis in the absence of TNF in neurosecretory cells (NSC) of young and old mice. For this purpose, we determined immunohistochemically expression of apoptosis markers caspase-8, -9. Bax, Bcl2, Mcl1, neuropeptide vasopressin, and the apoptosis level in hypothalamus in tnf-knockout mice of different ages as compared with mice with unchanged level of TNF synthesis. It was shown that the apoptosis activation observed during aging did not depend on the tnf gene, and apoptosis at aging was caspase-dependent. It has been revealed that at aging in mouse NSC the external cell death pathway with participation of caspase-8 is activated. The pathways mediating cell death in different neurosecretory centers at aging are different. Thus, in supraoptic nucleus (SON), in all studied animal groups, animal groups, an important cause of the NSC apoptosis is Bax. In paraventricular nucleus (PVN), of the greater importance is a decrease of the antiapoptotic protection. Hence, misbalance of synthesis of proteins of the Bcl-2 family plays an important role in development of senescent apoptosis.
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PMID:[Ontogenetic peculiarities of regulation of apoptosis in hypothalamic neurosecretory cells in thf-knockout mice]. 1988

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and an agonistic monoclonal antibody to TRAIL-R1 (TRAIL-R1 mAb) induce apoptosis and show anti-proliferative activity in vitro and in vivo. However, some TRAIL-R1-expressing cell lines are not sensitive to either TRAIL-R1 mAb or TRAIL. We have identified four genes (STK17B, SP140L, CASP8, and AIM1) whose expression levels differ significantly between TRAIL-R1 mAb-sensitive and resistant cell lines. Using the expression levels of these genes, we predicted TRAIL-R1 mAb and TRAIL sensitivity in our test cell lines with 75% (9/12) and 84% (21/25) accuracy, respectively. Knockdown of STK17B in TRAIL-R1 mAb-sensitive cells augmented Bcl-2 expression and suppressed TRAIL-R1 mAb-induced apoptosis. Our results may be useful for predicting the response of cancers to TRAIL-agonistic drugs in the clinic.
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PMID:Biomarkers for predicting the sensitivity of cancer cells to TRAIL-R1 agonistic monoclonal antibody. 2005 15


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