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Interference of Fisetin with Targets of the Nuclear Factor-κB Signal Transduction Pathway Activated by Epstein-Barr Virus Encoded Latent Membrane Protein 1
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《Asian Pacific journal of cancer prevention》2014,15(22):9835-9839
Fisetin is an effective compound extracted from lacquer which has been used in the treatment of variousdiseases. Preliminary data indicate that it also exerts specific anti-cancer effects. However, the manner in whichfisetin regulates cancer growth remains unknown. In this study, we elucidated interference of fisetin with targetsof the nuclear factor κB signal transduction pathway activated by Epstein-Barr virus encoding latent membraneprotein 1 (LMP1)in nasopharyngeal carcinoma (NPC) cells, Results showed that fisetin inhibited the survivalrate of CNE-LMP1 cells and NF-κB activation caused by LMP1. Fisetin also suppressed nuclear translocationof NF-κB (p65) and IκBα phosphorylation, while inhibiting CyclinD1, all key targets of the NF-κB signaltransduction pathway. It was suggested that interference effects of fisetin with signal transduction activated byLMP1 encoded by the Epstein-Barr virus may play an important role in its anticancer potential. 相似文献
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Bin Zhou Li Rao Yi Li Linbo Gao Yanyun Wang Yu Chen Hui Xue Yaping Song Ying Peng Miao Liao Lin Zhang 《Cancer letters》2009
Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. Nuclear factor-κB (NF-κB)-activation plays critical roles in Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) mediated tumorigenesis in NPC. A functional insertion/deletion polymorphism (−94 insertion/deletion ATTG) in the promoter of NFKB1 gene, which encodes the p50 subunit of NF-κB protein complex, was recently identified. This study found that the frequency of ATTG2 allele in NPC patients was significantly higher than that in control subjects (66% vs. 57.1%, p = 0.015, OR = 1.453), suggesting that the functional NFKB1 promoter polymorphism is associated with increased risk for NPC. 相似文献
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Zhi Y Cheng Xiao L Guo Xiao Y Yang Zhi Y Niu Shi H Li Su Y Wang Hao Chen Ling Pan 《Journal of experimental & clinical cancer research : CR》2008,27(1):1-9
Background
Clear cell renal cell carcinoma (ccRCC) is the most frequently encountered tumor in the adult kidney. Many factors are known to take part in the development and progression of this tumor. Nuclear factor kappa B (NF-κB) is a family of the genes that includes five members acting in events such as inflammation and apoptosis. In this study, the role of NF-κB (p50 subunit) in ccRCC and its relation to angiogenesis and apoptosis were investigated.Methods
Formalin-fixed and paraffin embedded tissue blocks from 40 patients with ccRCC were studied. Expressions of NF-κB (p50), VEGF, EGFR, bc1-2 and p53 were detected immunohistochemically. The relationship of NF-κB with these markers and clinicopathological findings were evaluated.Results
The expression of NF-κB was detected in 35 (85%), VEGF in 37 (92.5%), EGFR in 38 (95%), bc1-2 in 33 (82.5%) and p53 in 13 (32.5%) of 40 ccRCC patients. Statistical analyses revealed a significant relation between NF-κB expression and VEGF (p = 0.001), EGFR (p = 0.004), bc1-2 (p = 0.010) and p53 (p = 0.037). There was no significant correlation between NF-κB and such parameters as tumor grade, stage, age and sex.Conclusion
The results of this study indicated that in ccRCC cases NF-κB was associated with markers of angiogenesis and apoptosis such as VEGF, EGFR, bc1-2 and p53. In addition, the results did not only suggest a close relationship between NF-κB and VEGF, EGFR, bc1-2 and p53 in ccRCC, but also indicate that NF-κB was a potential therapeutic target in the treatment of ccRCC resistant to chemotherapy. 相似文献6.
Shumin Zhang Haiyen E Zhau Adeboye O Osunkoya Shareen Iqbal Xiaojian Yang Songqing Fan Zhengjia Chen Ruoxiang Wang Fray F Marshall Leland WK Chung Daqing Wu 《Molecular cancer》2010,9(1):1-13
Background
Nuclear factor-κB (NF-κB) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-κB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-κB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-κB in advanced thyroid cancer cell lines.Results
Three pharmacologic inhibitors of NF-κB differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-κB inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-κB signaling by overexpression of a dominant-negative IκBα (mIκBα). These studies revealed decreased cell growth in only one of five thyroid cancer cell lines (8505C), which occurred through a block in the S-G2/M transition. Resistance to TNFα-induced apoptosis was observed in all cell lines, likely through an NF-κB-dependent mechanism. Inhibition of NF-κB by mIκBα sensitized a subset of cell lines to TNFα-induced apoptosis. Sensitive cell lines displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, defining a potential mechanism of response. Finally, NF-κB inhibition by mIκBα expression differentially reduced thyroid cancer cell invasion in these thyroid cancer cell lines. Sensitive cell lines demonstrated approximately a two-fold decrease in invasion, which was associated with differential expression of MMP-13. MMP-9 was reduced by mIκBα expression in all cell lines tested.Conclusions
These data indicate that selective inhibition of NF-κB represents an attractive therapeutic target for the treatment of advanced thyroid. However, it is apparent that global regulation of thyroid cancer cell growth and invasion is not achieved by NF-κB signaling alone. Instead, our findings suggest that other important molecular processes play a critical role in defining the extent of NF-κB function within cancer cells. 相似文献7.
背景与目的:探讨倍半萜烯内酯化合物对人鼻咽癌(nasopharyngeal carcinoma,NPC)细胞内核因子-κB(NF-κB)信号转导活化的影响。材料与方法:采用小白菊内酯(parthenolide,PN)作为受试物,以对PN诱导转归敏感的CNE1细胞给予TNF-α预诱导建立模型,PN处理后提取胞质和胞核蛋白,分别检测IκBα降解、NF-κB p65亚单位活化后核内迁移,电泳迁移率改变试验(EMSA)检测核内活化NF-κB的DNA结合活性。进行PN剂量和作用时间依赖关系分析。结果:阴性对照组IκBα蛋白存在于胞质中,PN处理组使TNF-α诱导的胞质IκBα蛋白降解被抑制、胞核内蛋白含量减少;相应地,阴性对照组p65亚单位在胞质中含量高于胞核内,PN处理组抑制TNF-α诱导的胞质p65核转位;同步进行的EMSA可见,PN处理组NF-κB核结合活性比TNF-α诱导组明显降低。随PN处理时间(0.5~4h)和剂量(5~25μmol/L)增加,胞质中IκBα蛋白降解的抑制作用增强(其蛋白含量增加),胞核内p65亚单位蛋白减少,EMSA结合活性降低,呈明显的剂量和时间依赖性(P均<0.05)。结论:PN可影响NPC细胞内NF-κB因子的活化,提示PN对TNF-α诱导NF-κB信号的抑制作用可能是PN诱导NPC细胞凋亡敏感性的分子机制之一。 相似文献
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Teng?Huang Li?Yin Jing?Wu Jia-Jia?Gu Jian-Zhong?Wu Dan?Chen Hong-Liang?Yu Kai?Ding Nan?Zhang Ming-Yu?Du Lu-Xi?Qian Zhi-Wei?Lu Xia?He
Background
Nasopharyngeal carcinoma (NPC) is among the most common squamous cell carcinoma in South China and Southeast Asia. Radiotherapy is the primary treatment for NPC. However, radioresistance acts as a significant factor that limits the efficacy of radiotherapy for NPC patients. Growing evidence supports that microRNAs (miRNAs) play an important role in radiation response.Methods
Real-time quantitative PCR was used to analyze the expression of miR-19b-3p in NPC cell lines and NP69. miR-19b-3p expression profiles in NPC tissues were obtained from the Gene Expression Omnibus database. The effect of miR-19b-3p on radiosensitivity was evaluated by cell viability assays, colony formation assays and in vivo experiment. Apoptosis and cell cycle were examined by flow cytometry. Luciferase reporter assay was used to assess the target genes of miR-19b-3p. Expression of target proteins and downstream molecules were analyzed by Western blot.Results
miR-19b-3p was upregulated in NPC and served as an independent predictor for reduced patient survival. Radioresponse assays showed that miR-19b-3p overexpression resulted in decreased sensitivity to irradiation, whereas miR-19b-3p downregulation resulted in increased sensitivity to irradiation in vitro. Moreover, miR-19b-3p decreased the sensitivity of NPC cells to irradiation in vivo. Luciferase reporter assay confirmed that TNFAIP3 was a direct target gene of miR-19b-3p. Knockdown of TNFAIP3 reduced sensitivity to irradiation, whereas upregulation of TNFAIP3 expression reversed the inhibitory effects of miR-19b-3p on NPC cell radiosensitivity. Mechanistically, we found that miR-19b-3p increased NPC cell radioresistance by activating the TNFAIP3/ NF-κB axis.Conclusions
miR-19b-3p contributes to the radioresistance of NPC by activating the TNFAIP3/ NF-κB axis. miR-19b-3p is a determinant of NPC radioresponse and may serve as a potential therapeutic target in NPC treatment.9.
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Franz Rödel Benjamin Frey Udo Gaipl Reinhard Voll Claus Rödel 《Radiotherapy and oncology》2010,97(2):346-351
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目的 探讨LMP1 对鼻咽癌上皮样细胞系CNE1 (nasopharyngeal carcinoma epithelioid cell lines , CNE ) 中端粒酶活性的影响及相关调控机制。方法 分别采用SP 法、RT2PCR 法和PCR2ELISA 法检测鼻 咽癌细胞CNE1 、CNE1GL (转染了目的基因质粒PAT2GFP2LMP1 的CNE1 细胞株) 和CNE22Z 中LMP1 、 NF2κB、c2myc 和hTERT 的表达、hTERT mRNA 水平和端粒酶活性。结果 (1) CNE1GL 与CNE1 细胞相 比,LMP1 、NF2κB、c2myc、hTERT 的表达水平均高于CNE1 细胞中各指标的表达,差异有统计学意义( P < 0. 01) 。CNE22Z和CNE1GL 、CNE1 相比,细胞中各指标的表达水平均最高( P < 0. 01 或P < 0. 05) 。 CNE1GL 细胞中,LMP1 与NF2κB、NF2κB 与c2myc 及LMP1 与c2myc 的表达之间均呈显著正相关( P < 0. 01或P < 0. 05) 。(2) hTERT mRNA 水平在CNE1GL 细胞明显高于CNE1 细胞,差异有统计学意义( P < 0. 01) ;在三种细胞中,CNE22Z细胞中hTERT mRNA 水平最高( P < 0. 01) 。(3) CNE1GL 细胞中的端粒酶 活性明显高于CNE1 细胞,差异有统计学意义( P < 0. 05) ;CNE1GL 细胞中的端粒酶活性略低于CNE22Z 细胞( P > 0. 05) ;CNE22Z细胞中的端粒酶活性明显高于CNE1 细胞( P < 0. 01) 。结论 在CNE1GL 细胞 中,LMP1 通过激活hTERT 转录而激活端粒酶。此调控过程可能和NF2κB 激活,NF2κB 进而上调c2myc 表达水平,c2myc 提高hTERT 转录水平有关。LMP1 激活端粒酶可能是鼻咽癌癌变过程中的重要事件。 相似文献
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Objective:The aim of this study was to investigate whether astrocyte elevated gene 1 (AEG1) regulates COX-2 expression in human hepatoma HepG2 cells and related pathways involved in this process. Methods:Human hepatoma HepG2 cells were transfected with pcDNA3.1(-)-AEG1 plasmid or psilencer2.0-AEG1-shRNA1 plasmid to up/down-regulate AEG1 expression, pcDNA3.1(-) and psilencer 2.0 empty vector plasmids were transfected respectively as control. Real-time RT-PCR was carried out to measure the expression levels of AEG1 and COX-2 mRNA. The expression levels of AEG1 and COX-2 protein were detected by Western blot. NF-κB signaling was blocked by PDTC, and AP-1 signaling was blocked by curcumin. Results:AEG1 mRNA and protein levels were increased after pcDNA3.1(-)-AEG1 transfection, and decreased after psilencer2.0-AEG1-shRNAs transfection. COX-2 mRNA and protein levels were increased in AEG1-overexpressing cells and decreased in AEG1-knockdown cells. Phosphorylations of p65 and c-jun were up-regulated in AEG1-overexpressing cells. Both PDTC and curcumin reduced COX-2 expression in HepG2 cells with AEG1 overexpression. Conclusion:AEG1-overexpressing and-knockdown HepG2 cells are established successfully. AEG1 could induce COX-2 expression though activating NF-κB and AP-1 in human hepatoma HepG2 cells. 相似文献
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Tudor CS Dawson CW Eckhardt J Niedobitek G Büttner AC Seliger B Hartmann A Buettner M 《British journal of cancer》2012,106(12):1980-1988
Background:
Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) up-regulates the human leukocyte antigen (HLA) class I antigen presentation machinery (APM). This appears counterintuitive with immune evasion in EBV-associated tumours like nasopharyngeal carcinoma (NPC).Methods:
Latent membrane protein 1-transfected epithelial cell lines were used as a model system to study the impact of LMP1 and c-Myc on HLA class I components. The expression of components of the HLA class I APM, c-Myc and Ki-67 was analysed in LMP1+ and LMP1− NPC by immunohistochemistry.Results:
In epithelial cells, LMP1 up-regulated HLA class I APM. This effect could be counteracted by c-Myc, which itself was up-regulated by LMP1 apparently through IL6 induction and Jak3/STAT3 activation. Studies of NPC biopsies revealed down-regulation of HLA class I APM expression. No difference was observed between LMP1+ and LMP1− NPC. However, expression of Ki-67 and c-Myc were up-regulated in LMP1+ tumours.Conclusion:
These findings raise the possibility that c-Myc activation in NPC might antagonise the effect of LMP1 on HLA class I expression thus contributing to immune escape of tumour cells. 相似文献17.
Horikawa T Yoshizaki T Kondo S Furukawa M Kaizaki Y Pagano JS 《British journal of cancer》2011,104(7):1160-1167
Background:
Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) is distinctive among head-and-neck cancers in its undifferentiated histopathology and highly metastatic character. We have recently investigated the involvement of epithelial–mesenchymal transition (EMT) in NPC. In a previous study, we found a close association of expression of LMP1, the principal EBV oncoprotein, with expression of Twist and induction of EMT.Methods:
We analysed expression of Snail in 41 NPC tissues by immunohistochemistry. The role of Twist as well as Snail in EMT of NPC was investigated by using NP69SV40T human nasopharyngeal cells.Results:
In NPC tissues, overexpression of Snail is associated with expression of LMP1 in carcinomatous cells. In addition, expression of Snail positively correlated with metastasis and independently correlated inversely with expression of E-cadherin. Expression of Twist had no association with expression of E-cadherin. Further, in a human nasopharyngeal cell line, LMP1 induces EMT and its associated cellular motility and invasiveness. Expression of Snail is induced by LMP1 in these cells, and small hairpin RNA (shRNA) to Snail reversed the cellular changes. By contrast, Twist did not produce EMT in these nasopharyngeal cells.Conclusions:
This study strengthens the association of EMT with the metastatic behaviour of NPC. These results suggest that induction of Snail by the EBV oncoprotein LMP1 has a pivotal role in EMT in NPC. 相似文献18.
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Jason Ho Ting Wong Vivian Wai Yan Lui Kazuo Umezawa Yeung Ho Elaine Yue Ling Wong Margaret Heung Ling Ng Suk Hang Cheng Chi Man Tsang Sai Wah Tsao Anthony Tak Cheung Chan 《Cancer letters》2010
Despite the demonstrated constitutive activation of NF-κB in nasopharyngeal carcinoma (NPC), the therapeutic potential of targeting this pathway has not been investigated. Here, we employed a small molecule inhibitor of NF-κB, DHMEQ (which mainly blocks nuclear translocation of activated NF-κB) and demonstrated significant inhibition of NPC cell proliferation, migration, invasion, as well as anchorage-independent growth. These antitumor effects were associated with induction of G2/M cell cycle arrest and apoptosis, and downregulation of NF-κB target genes (EGFR, cyclin D1 and survivin). This first demonstration of therapeutic benefits of NF-κB targeting in NPC implicates the importance of targeting this pathway in NPC. 相似文献
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目的探讨hsp27基因对鼻咽癌细胞增殖的影响及其机制。方法利用实时定量PCR检测NP460(正常鼻咽部上皮细胞株)、CNE2(低分化鼻咽癌细胞株)及S18(CNE2的高转移亚克隆)的hsp27转录水平,利用慢病毒转染技术在hsp27转录水平较低的CNE2中过表达hsp27,利用小干扰RNA技术抑制S18细胞内的hsp27,用MTT技术检测过表达或抑制hsp27后细胞增殖速率的变化,同时检测转录因子NF-κB的转录水平的变化,分析hsp27影响鼻咽癌细胞增殖速率的可能机制。结果(1)三种细胞株中的内源性hsp27水平为S18>CNE2>NP460,差异具有统计学意义。(2)在CNE2细胞中过表达hsp27基因后,细胞的增殖速率明显加快,NF-κB转录水平明显上调。(3)抑制S18细胞内的hsp27基因后,细胞的增殖速率明显减缓,NF-κB转录水平明显下调。结论hsp27基因可能通过调节NF-κB信号通路而对鼻咽癌细胞发挥明显的促增殖作用,可设计针对hsp27基因的抗鼻咽癌分子治疗策略。 相似文献