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)

We have investigated apoptosis related gene expression in tumour cells, phenotype and function of blood mononuclear cells at diagnosis in relation to clinical response in three patients with nasopharyngeal carcinoma (NPC). We have focused our study on the Epstein Barr virus latent membrane protein-1 (LMP-1) and Bcl-2 expression in the tumour cells, the essential signal-transducing zeta molecule of T cell receptor (TcR zeta) and cellular mediated cytolysis of the blood mononuclear cells. The carcinoma cells of the patients were Bcl-2 negative. They were heterogeneous with regard to the expression of LMP-1 and the number of proliferating or apoptotic cells. Decrease in the expression of mature T cells (CD3, CD4, and CD8), TcR zeta and cellular mediated cytotoxicity was detected in blood mononuclear cells of the patients. IL-2 up-regulated these phenotypes and the cytolytic capacity of the blood mononuclear cells. The patient with LMP-1 negative carcinoma cells, down-regulated TcR zeta expression and impaired IL-2 mediated cytolysis, had the worst clinical outcome. Another patient with low apoptotic, highly proliferating and LMP-1 positive carcinoma cells had recurrent disease only in the irradiated area. Interestingly, NPC with high apoptotic and few LMP-1 expressing cells was detected in the patient with a normal level of TcR zeta expression and cytolytic functions in blood mononuclear cells at the time of diagnosis. After combination treatment with chemotherapy followed by radiotherapy, this patient is still alive with complete remission and disease-free at 36 months. Suppression of the immunological functions may occur in NPC patients. Our study suggests that the immunological functions and apoptosis related gene expression in the carcinoma cells may be used as prognostic factors and help in the decision of therapy of patients with nasopharyngeal cancer.
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PMID:Alteration of cellular mediated cytotoxicity, T cell receptor zeta (TcR zeta) and apoptosis related gene expression in nasopharyngeal carcinoma (NPC) patients: possible clinical relevance. 1081 Apr 2

Nasopharyngeal carcinoma is closely associated with Epstein-Barr virus (EBV) and the EBV encoded latent membrane protein-1 expression (LMP1) is commonly found in the tumour cells. LMP1 has been shown to be involved in modulation of cell growth in B cells but the biological properties of LMP1 expression in nasopharyngeal carcinoma cells are less defined. In this study, a full length LMP1 gene was introduced into an EBV negative nasopharyngeal carcinoma cell line, CNE2, and five LMP1-expressing clones were isolated. Expression of LMP1 did not confer cell growth advantage in CNE2 cells; instead, it induced growth inhibition both in vitro and in vivo. In addition, the LMP1 transfected cells were more susceptible to cisplatin-induced cell death and showed 1.4-4.0-fold increased sensitivity to cisplatin compared to the vector infected control clones. The effect of LMP1 on the balance of Bcl-2 and Bax ratio may play a role in inducing susceptibility to cisplatin-induced cell death. These results demonstrated that LMP1 did not confer growth advantage in CNE2 cells, suggesting that expression of LMP1 may not be crucial in sustaining cell growth in established cell lines. Alternatively, LMP1 alone may not be sufficient to facilitate nasopharyngeal carcinoma cell growth and additional oncogenic factors may be needed along with LMP1 in modulating the malignant property of nasopharyngeal carcinoma.
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PMID:Latent membrane protein-1 of Epstein-Barr virus inhibits cell growth and induces sensitivity to cisplatin in nasopharyngeal carcinoma cells. 1174 60

Nasopharyngeal carcinomas (NPCs) are consistently associated with the Epstein-Barr virus (EBV). As Bcl-2 and Bcl-X are co-expressed in EBV-transformed B-lymphocytes, we attempted to determine their status in malignant NPC cells. A retrospective series of 100 NPC specimens from untreated Tunisian patients was investigated by immuno-histochemistry. Twenty seven of the patients were below 30 years old and therefore classified in the "juvenile" form of north African NPCs. Bcl-2 and Bcl-X expression was assessed semi-quantitatively using a score based on the percentage of positive cells and staining intensity. Intense Bcl-X expression was detected in malignant cells of 100% biopsy samples with similar scores for patients below 30 years or those aged 30 or over. Bcl-2 was detected in 89% biopsies but its expression differed considerably between the samples. The average Bcl-2 score was much lower for patients under 30 years (4.4+/-1.5 compared to 6.5+/-2 for older patients; P<10(-6)). Multivariate analysis demonstrated that no other clinical parameter, except the primary tumor size, was correlated to the Bcl-2 score. Bcl-X and Bcl-2 are co-expressed in 89% of NPCs whereas their expression is mutually exclusive in other head and neck carcinomas (particularly squamous cell carcinomas, SCC). The constantly high expression of Bcl-X is consistent with it being induced by the EBV protein Epstein-Barr nuclear antigen 1 (EBNA1), as recently reported in a murine model. The contrasted levels of Bcl-2 expression in the two age groups strengthen the hypothesis that these clinical forms result from distinct oncogenic mechanisms.
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PMID:Similar BCL-X but different BCL-2 levels in the two age groups of north African nasopharyngeal carcinomas. 1289 71

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP-1), is expressed in the majority of NPCs. LMP-1 upregulates antiapoptotic genes, including bcl-2, and Bcl-2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl-2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666-1 line, a stably infected NPC-derived line that co-expresses LMP-1 and Bcl-2. We have shown that G3139 treatment of C666-1 in vitro caused sequence-dependent suppression of Bcl-2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days x 5 doses) delayed engraftment and significantly inhibited growth of established C666-1 xenografts in SCID mice compared to control oligo-treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days x 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real-time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl-2 levels were significantly decreased in G3139-treated animals. Our studies have demonstrated that the Bcl-2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666-1, and in combination with CDDP, is curative in C666-1 NPC xenograft tumors in vivo. The sequence-dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl-2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC.
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PMID:Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice. 1647 27

BHRF1, an early gene product of Epstein-Barr virus (EBV), is structurally and functionally homologous to Bcl-2, a cellular anti-apoptotic protein. BHRF1 has been shown to protect cells from apoptosis induced by numerous external stimuli. Nasopharyngeal carcinoma is an epithelial cancer associated closely with EBV infection. Specific proteins that might interact with and modulate the BHRF1 anti-apoptotic activity in normal epithelial cells are of interest. Therefore, a cDNA library derived from normal human foreskin keratinocytes was screened by the yeast two-hybrid system and a cellular gene encoding human vaccinia virus B1R kinase-related kinase 2 (VRK2) was isolated. Interaction between the cellular VRK2 and viral BHRF1 proteins was further demonstrated by glutathione S-transferase pull-down assays, confocal laser-scanning microscopy and co-immunoprecipitation. Analyses of VRK2-deletion mutants revealed that a 108 aa fragment at the C terminus was important for VRK2 to interact with BHRF1. For BHRF1, aa 1-18 and 89-142 were crucial in interacting with VRK2 and these two regions are counterparts of Bcl-2 homology domains 4 and 1. Overexpressed VRK2 alone showed a modest effect in anti-apoptosis and appeared to enhance cell survival in the presence of BHRF1. However, this enhancement was not observed when VRK2 was co-expressed with Bcl-2. The results indicate that human VRK2 interacts specifically with EBV BHRF1 and that the interaction is involved in protecting cells from apoptosis.
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PMID:Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival. 1696 44

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. It has been reported that overexpression of antiapoptotic Bcl-2 family proteins in NPC has caused the lack of long-term efficacy of conventional therapies. Apogossypolone (ApoG2), a novel small-molecule inhibitor of antiapoptotic Bcl-2 family proteins, has been discovered as the optimized derivative of gossypol. In this study, we found that in NPC cells, ApoG2 totally blocked the antiapoptotic function of Bcl-2 family proteins without affecting the expression levels of these proteins. ApoG2 selectively inhibited proliferation of 3 NPC cell lines (C666-1, CNE-1 and CNE-2) that highly expressed the antiapoptotic Bcl-2 proteins. This inhibitory activity was associated with release of cytochrome c, activation of caspase-9 and caspase-3 and apoptosis of sensitive NPC cells. However, ApoG2 had no obvious inhibitory effect on NPC cell line HONE-1, which expressed antiapoptotic Bcl-2 and Bcl-xL at a low level. We further found that ApoG2 effectively suppressed tumor growth of NPC xenografts in nude mice and enhanced the antitumor effect of CDDP (cisplatin) on NPC cells in vitro and in vivo. Immunohistochemical results showed that the expression of CD31 decreased after ApoG2 treatment, which suggested inhibition of angiogenesis in NPC xenografts. Our findings strongly suggest that ApoG2 may serve as a novel inhibitor of Bcl-2 family proteins and, by targeting these proteins, may become a promising drug for the treatment of NPC.
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PMID:ApoG2, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts. 1871 28

Volatile oils from Centipeda minima extracted by steam distillation (SD) and supercritical fluid extraction (SFE) were investigated for their antiproliferative effects on the human nasopharyngeal cancer CNE cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay results showed that CNE cells were more susceptible to the SFE oil than to the SD oil. The IC50 values of the SFE oil were 56.6, 8.7 and 5.2 microg/mL after 24-, 48- and 72-h of treatment, respectively, whereas those of the SD oil were 123.5 microg/mL (24 h), 97.1 microg/mL (48 h) and 83.3 microg/mL (72 h). Mechanistic investigation revealed that SFE oil induced CNE cell death via induction of apoptosis by regulating the expression of the Bcl-2 family of proteins, resulting in the dysfunction of mitochondria, leading to the release of cytochrome c into the cytosol, which then activated caspase-9, and subsequently cleaved caspases-3 and -7. This study provided strong evidence for the anti-NPC potential of the SFE oil from C. minima.
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PMID:Antiproliferative effects of volatile oils from Centipeda minima on human nasopharyngeal cancer CNE cells. 2018 42

1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd) is a ribose-modified nucleoside analog of cytidine with potent anticancer activity in several cancers. The main antitumor mechanism of this promising RNA-directed nucleoside anti-metabolite is efficient blockade of RNA synthesis in cancer cells. Here, we examined the therapeutic potential of this RNA-directed anti-metabolite in in vitro models of nasopharyngeal cancer (NPC). In a panel of 6 NPC cell lines, ECyd effectively inhibited cellular proliferation at nM concentrations (IC(50): approximately 13-44nM). Moreover, cisplatin-resistant NPC cells were highly sensitive to ECyd (at nM concentration). The ECyd-mediated growth inhibition was associated with G(2)/M cell cycle arrest, PARP cleavage (a hallmark of apoptosis) and Bcl-2 downregulation, indicating induction of apoptosis by ECyd in NPC cells. Unexpectedly, ECyd-induced significant downregulation of TIGAR, a newly described dual regulator of apoptosis and glycolysis. More importantly, this novel action of ECyd on TIGAR was accompanied by marked depletion of NADPH, the major reducing power critically required for cell proliferation and survival. We hypothesized that ECyd-induced TIGAR downregulation was crucially involved in the antitumor activity of ECyd. Indeed, overexpression of TIGAR was able to rescue NPC cells from ECyd-induced growth inhibition, demonstrating a novel mechanistic action of ECyd on TIGAR. We demonstrated for the first time that an RNA-directed nucleoside analog, ECyd, exerts its antitumor activity via downregulation of a novel regulator of apoptosis, TIGAR. Moreover, ECyd may represent a novel therapy for NPC.
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PMID:An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation. 2021 41

Nasopharyngeal carcinoma (NPC) is an unusual head and neck cancer because of its unequal geographical distribution and its consistent association with the Epstein-Barr virus (EBV). This malignant tumor poses a serious public health problem in many countries, especially in Southeast Asia and North Africa where the recorded incidence are highest. During the past decade, a growing number of studies were undertaken to define the molecular basis of NPC. However, the analysis of several clinical and biological parameters of North African and Southeast Asian NPCs has shown notable differences, suggesting that they could result from a distinct combination of etiological factors. One intriguing characteristic of North African NPC, concerns its bimodal age distribution with a secondary peak of incidence in the range of 15-25 years, not observed in Asian NPC. In this juvenile form of NPC, immuno-histochemistry assay has shown that the two key proteins controlling the apoptotic-survival balance p53 and Bcl-2 are less frequently expressed whereas the transmembrane tyrosine-kinase receptor c-kit and the main EBV oncoprotein LMP1 were more abundant. In addition, the EBV serological alterations are less informative for the diagnosis of the juvenile compared to the adult form. In addition, most North African NPCs contain EBV strains with genetic polymorphisms distinct from those described in the Southeast Asia series (predominance of F, D, H1-H2, XhoI+ and f, C, H, XhoI- respectively). In contrast, studies relating on tumor chromosomal alterations or aberrant promoter methylation result in data very similar to those obtained from the Southeast Asia series, supporting the concept of a common molecular basis for all NPC regardless of patient geographic origin.
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PMID:[North African and Southeast Asian nasopharyngeal carcinomas: between the resemblance and the dissemblance]. 2038 21

High incidence of lymph node spread and distant metastasis make poor prognosis in human nasopharyngeal carcinoma (NPC). Therefore, better treatments for NPC are needed. This study investigated the anticancer activity of 6-O-angeloylenolin, a plant-derived sesquiterpene lactone, on human nasopharyngeal cancer (CNE) cells. 6-O-Angeloylenolin was found to significantly inhibit the proliferation of CNE cells. The rate of inhibition was comparable to that of cisplatin, a well known chemotherapeutic agent used to treat NPC. Further mechanistic studies revealed that 6-O-angeloylenolin caused cell-cycle arrest in the S and G2/M phases and, subsequently, the induction of apoptosis. Rapid repressions of cyclin D1, cyclin D3, p27, cdc25c and p-cdc25c (Ser216) were observed after 1-h treatment, followed by decreases in the expression of CDK4, cdc2 and p-cdc2 (Tyr15) after 12h. Down-regulations of p-Rb (Ser780), p21(Waf1/Cip1), cyclin A, and cyclin E were also detected as later events. Two early events that marked the occurrence of apoptosis were phosphatidylserine exposure and mitochondria membrane potential depletion, which occurred after 12h of treatment, while a sub-G1 peak was also detected after 36-h treatment. Apoptosis induction was further confirmed by other apoptotic features, including nuclear fragmentation, and PARP cleavage. Moreover, 6-O-angeloylenolin caused the release of cytochrome c and AIF to the cytosol by regulating the expression of the Bcl-2 family proteins. However, pretreatment of the general caspase inhibitor failed to attenuate the apoptosis induction effect, suggesting that apoptosis induction of 6-O-angeloylenolin was independent of caspase activation. While 6-O-angeloylenolin also triggered the activation of Akt, ERK and JNK, only the JNK inhibitor significantly decreased the extent of cell death and apoptosis in CNE cells. Taken together, these results suggest the potential applicability of 6-O-angeloylenolin as a candidate for NPC treatment.
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PMID:6-O-Angeloylenolin induced cell-cycle arrest and apoptosis in human nasopharyngeal cancer cells. 2119 22


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