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)

Indirubin-3'-monoxime (I3M) is a derivative of indirubin, an active component from a Chinese medicinal recipe with known anti-cancer function. I3M has been well established as a cyclin-dependent kinase (CDK) inhibitor, while the molecular mechanism underlying I3M-induced apoptosis has not been fully elucidated. In this study, we focused on the critical role of the pro-apoptosis Bcl-2 family members in I3M-induced apoptosis. We first observed I3M-induced apoptosis in a time- and dose-dependent manner in three different types of human cancer cells-cervical cancer HeLa, hepatoma HepG2 and colon cancer HCT116. Induction of the caspase cascade for both the extrinsic and intrinsic pathways was demonstrated, including caspase-8, -9 and -3 activation. Initiation of the death receptor pathway started with enhanced surface expression of DR4 and DR5, as well as increased total protein level, which correlated with the up-regulation of p53 and its transcriptional activity. Importantly, we found in HeLa cells that caspase-8 activation resulted in Bid cleavage, followed by Bax conformational change and hence the amplification of the apoptotic signals through the mitochondrial pathway. Consistently, stable knockdown of Bid abrogated I3M-induced Bax conformational change and cell death. Moreover, ectopic expression of a viral caspase inhibitor (CrmA) or Bcl-2 partially protected I3M-induced apoptosis. In conclusion, our results indicate that I3M mainly elicites apoptosis through extrinsic pathway with type II response mediated by the pro-apoptotic Bcl-2 family members (Bid and Bax).
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PMID:Critical role of Bid and Bax in indirubin-3'-monoxime-induced apoptosis in human cancer cells. 1837 73

Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-X(L), survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII-positive blood vessels and hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappaB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms. 1872 80

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

Ubiquitin carboxy terminal hydrolase-L1 (UCH-L1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Previous research showed that UCH-L1 was expressed in mouse retinal cells and testicular germ cells, and its function was associated with apoptosis. But it is still unclear whether UCH-L1 is concerned with apoptosis in tumor cells. In order to clarify the role of UCH-L1 in tumor cells, multi-drug resistance (MDR) human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We transfected pcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively. Using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, western blot, Hoechst 33258 staining assay and flow cytometry, we found that over-expression of UCH-L1 in MCF7 cells induced apoptosis. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Moreover, to explore the mechanism underling these observations, we further investigated the expression of phospho-Akt and its downstream signal phospho-IkB-alpha and other signal molecules including Fas, Fas-L, Trail, DR4, DR5, Bax, cytochrome C, active caspase-3, phospho-p53, phospho-Mdm-2, Bcl-2, Bcl-xL, p21 and p27. The results indicated that the process of apoptosis triggered by UCH-L1 is, at least in part, probably through Phosphoinositide 3-kinase (PI3K)/Akt signal pathway. Our findings suggest that modulating the ubiquitination and deubiquitination pathway could be a novel method for tumor therapy.
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PMID:Over-expression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancer cells. 1894 67

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

It is reported that the agonistic antibodies against death receptors 4 and 5 (DR4, DR5) are cytotoxic to various cancer cells. In the present study, the sensitivity of five human lung cancer cell lines to previously reported AD5-10 agonistic antibody against DR5 were investigated. Of these cell lines, A549 and small cell lung cancer showed a moderate sensitivity to AD5-10 and three other cell lines were resistant. Cell line H460 is resistant to AD5-10 despite a high level of cell-surface DR5 expression. We demonstrated that the resistance of H460 cells to AD5-10 was not related to the expression level of DR5, but the expression and cleavage of c-FLIP(L) in the cells. Inhibition of endogenous c-FLIP(L) expression by siRNA significantly enhanced AD5-10-induced cell death in these lung cancer cells. We further showed that this sensitizing effect was associated with decreased expression of Bcl-2 family proteins Bid and Bcl-X(L), change of mitochondrial membrane potential, release of cytochrome c from mitochondria, and caspase activation. Therefore, these data provide evidence that c-FLIP(L) is involved in the resistance of lung cancer cells to AD5-10-induced apoptosis. Moreover, immunohistochemistry on paraffin-embedded tissue revealed that c-FLIP(L) was expressed in 87.9% (29 of 33) of lung carcinoma tissues from the patients, but little in tissues from normal controls. This suggests that inhibition of c-FLIP(L) expression might be a potential strategy for lung cancer therapy, especially for those lung cancers resistant to the agonistic antibody against death receptors.
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PMID:Knockdown of c-FLIP(L) enhanced AD5-10 anti-death receptor 5 monoclonal antibody-induced apoptosis in human lung cancer cells. 1924 85

Local hyperthermia has been successfully used in the treatment of viral warts. However, the mechanism of action of hyperthermia has largely remained unclear. In this study we evaluated the effect of local hyperthermia on the induction of apoptosis in human keratinocytes, and expression of apoptosis-related genes in both condyloma acuminata (CA) and normal skin. The study showed that higher hyperthermia increased the number of apoptotic keratinocytes in CA and normal skin. The temperature-dependent increased expression of Fas and Bax were observed in both CA and normal skin. In contrast, the expression of Bcl-2 in CA was decreased at both transcriptional and translational levels. Furthermore, the transcriptional expression of DR4 and DR5 were increased in a temperature-dependent manner in CA, but not in normal skin. These results suggest that different mechanisms of action might be involved in hyperthermia induced apoptosis in CA and normal skin.
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PMID:Local hyperthermia induces apoptosis of keratinocytes in both normal skin and condyloma acuminata via different pathways. 1936 4

TRAIL (tumor necrosis factor (TNF) related apoptosis-inducing ligand) has been introduced as an extrinsic pathway inducer of apoptosis that does not have the toxicities of Fas and TNF. However, the therapeutic potential of TRAIL is limited because of many primary tumor cells are resistant to TRAIL. Despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity and efficiency. A major reason likely lies in the complexity of the interaction of TRAIL with its five receptors, of which only two DR4 and DR5 are death receptors. Binding of TRAIL with decoy receptors DcR1 and DcR2 or soluble receptor osteoprotegerin (OPG) fail to induce apoptosis. Here we describe design and expression in Escherichia coli of DR5-selective TRAIL variants DR5-A and DR5-B. The measurements of dissociation constants of these mutants with all five receptors show that they practically do not interact with DR4 and DcR1 and have highly reduced affinity to DcR2 and OPG receptors. These mutants are more effective than wild type TRAIL in induction of apoptosis in different cancer cell lines. In combination with the drugs targeted to cytoskeleton (taxol, cytochalasin D) the mutants of TRAIL induced apoptosis in resistant Hela cells overexpressing Bcl-2. The novel highly selective and effective DR5-A and DR5-B TRAIL variants will be useful in studies on the role of different receptors in TRAIL-induced apoptosis in sensitive and resistant cell lines.
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PMID:Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5. 1941 66

High intake of whole grain food has been suggested as an important factor for reducing the risk of colon cancer, owing to the abundance of indigestible fibers. Our findings demonstrated that, among various rice bran phenolic compounds tested, cycloartenyl ferulate (CF) showed the most prominent in vitro growth inhibition on human colorectal adenocarcinoma SW480, but had low toxicity on normal colon CCD-18-Co cells. The anticancer activity of CF was further illustrated by its ability to induce significant regression of SW480 xenograft in nude mice. CF elevated the death receptors DR4 and DR5 and triggered both the death receptor and the mitochondrial apoptosis pathways. Depletion of anti-apoptotic Bcl-2 and up-regulation of pro-apoptotic Bak were observed, accompanied by dissipation of the mitochondrial membrane potential and release of cyto c and SMAC/DIABLO from mitochondria into the cytosol. Bid was found to be cleaved by caspase-8, so that the death receptor pathway might be exaggerated by the mitochondrial pathway. Strikingly, we showed for the first time that CF also sensitized the metastatic and resistant colon cancer SW620 to TRAIL-induced apoptosis and the mechanisms involved at least enhanced activation of caspase-8 and -3. This study provides a clear evidence that the health-beneficial properties of whole grain consumption are not only limited by the presence of dietary fibers but also other molecules that can either act as a chemopreventive agent to directly induce tumor regression or as a sensitizer to enhance TRAIL-induced apoptosis in metastatic cancer cells.
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PMID:A rice bran polyphenol, cycloartenyl ferulate, elicits apoptosis in human colorectal adenocarcinoma SW480 and sensitizes metastatic SW620 cells to TRAIL-induced apoptosis. 1942 86

The purpose of this study was to examine whether histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; Zolinza/vorinostat) could sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant breast carcinoma in vivo. BALB/c nude mice were orthotopically implanted with TRAIL-resistant MDA-MB-468 cells and treated i.v. with SAHA, TRAIL, or SAHA followed by TRAIL for four times during first 3 weeks. The effects of drugs on tumor growth and markers of apoptosis, metastasis, and angiogenesis were examined. SAHA sensitized TRAIL-resistant xenografts to undergo apoptosis through multiple mechanisms. Whereas TRAIL alone was ineffective, SAHA inhibited growth of MDA-MB-468 xenografts in nude mice by inhibiting markers of tumor cell proliferation, angiogenesis, and metastasis and inducing cell cycle arrest and apoptosis. The sequential treatment of nude mice with SAHA followed by TRAIL was more effective in inhibiting tumor growth, angiogenesis, and metastasis and inducing apoptosis than SAHA alone, without overt toxicity. Treatment of nude mice with SAHA resulted in down-regulation of nuclear factor-kappaB and its gene products (cyclin D1, Bcl-2, Bcl-X(L), vascular endothelial growth factor, hypoxia-inducible factor-1alpha, interleukin-6, interleukin-8, matrix metalloproteinase-2, and matrix metalloproteinase-9) and up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa, PUMA, p21(CIP1), tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in tumor cells. Furthermore, control mice showing increased rate of tumor growth had increased numbers of CD31(+) or von Willebrand factor-positive blood vessels and increased circulating vascular endothelial growth factor receptor 2-positive endothelial cells compared with SAHA-treated or SAHA plus TRAIL-treated mice. In conclusion, sequential treatment with SAHA followed by TRAIL may target multiple pathways in tumor progression, angiogenesis, and metastasis and represents a novel therapeutic approach to treat breast cancer.
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PMID:Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice. 1950 67


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