摘要
背景:白藜芦醇已被证明在多种癌症类型中具有抗氧化和抗增殖特性。在这里我们证明H460肺癌细胞比人类支气管上皮细胞Beas-2B细胞更易于白藜芦醇治疗。白藜芦醇降低细胞活力和增殖,诱导H460细胞凋亡。观察到的凋亡伴随着过氧化氢(H2O2)产生,Bid,PARP和半胱天冬酶8活化的增加,以及pEGFR,pAkt,c-FLIP和NFkB蛋白表达的下调。此外,用HH2O2清道夫过氧化氢酶处理显着抑制白藜芦醇诱导的c-FLIP下调,caspase-8的活化和细胞凋亡。 H460细胞(FLIP细胞)中c-FLIP的过表达导致白细胞介素诱导的HH2O2产生的抑制,与H460细胞相比,白藜芦醇诱导的细胞凋亡显着增加。在FLIP细胞中,与H460细胞相比,过氧化氢酶处理没有拯救细胞免受白藜芦醇的细胞活力和细胞凋亡诱导的降低。白藜芦醇治疗也导致FLIP细胞的VEGF下调。此外,分别使用厄洛替尼和LY294002抑制pEGFR或pAkt,增强白藜芦醇对FLIP细胞活力和凋亡的负面影响。当FLIP细胞补充有EGF或用WT-AKT质粒转染时观察到相反的结果;导致白藜芦醇诱导的细胞凋亡降低20%。此外,用WT-AKT质粒转染导致促凋亡蛋白激活的抑制,c-FLIP和pAkt下调。 结论:总体而言,白藜芦醇通过蛋白酶体降解以EGFR依赖性方式特异性靶向pAkt和c-FLIP下调,诱导H460肺癌细胞凋亡。肺癌,白藜芦醇,凋亡,c-FLIP,Akt,过氧化氢。
关键词: 肺癌,白藜芦醇,凋亡,c-FLIP,Akt,过氧化氢。
图形摘要
Current Cancer Drug Targets
Title:Anti-Tumorigenic Effects of Resveratrol in Lung Cancer Cells Through Modulation of c-FLIP
Volume: 17 Issue: 7
关键词: 肺癌,白藜芦醇,凋亡,c-FLIP,Akt,过氧化氢。
摘要: Background: Resveratrol has been shown to have antioxidant and anti-proliferative properties in multiple cancer types. Here we demonstrate that H460 lung cancer cells are more susceptible to resveratrol treatment in comparison to human bronchial epithelial Beas-2B cells. Resveratrol decreases cell viability and proliferation, and induces significant apoptosis in H460 cells. The apoptosis observed was accompanied by an increase in hydrogen peroxide (H2O2) production, Bid, PARP and caspase 8 activation, and downregulation of pEGFR, pAkt, c-FLIP and NFkB protein expression. Furthermore, treatment with HH2O2 scavenger catalase significantly inhibited resveratrol-induced c-FLIP downregulation, caspase-8 activation and apoptosis. Overexpression of c-FLIP in H460 cells (FLIP cells) resulted in the inhibition of resveratrol-induced HH2O2 production, and a significant increase in resveratrolinduced apoptosis in comparison to H460 cells. In FLIP cells, catalase treatment did not rescue cells from a decrease in cell viability and apoptosis induction by resveratrol as compared to H460 cells. Resveratrol treatment also led to VEGF downregulation in FLIP cells. Furthermore, inhibition of pEGFR or pAkt using erlotinib and LY294002 respectively, enhanced the negative effect of resveratrol on FLIP cell viability and apoptosis. The reverse was observed when FLIP cells were supplemented with EGF, or transfected with WT-AKT plasmid; resulting in a 20% decrease in resveratrol-induced apoptosis. In addition, transfection with WT-AKT plasmid resulted in the inhibition of pro-apoptotic protein activation, and c-FLIP and pAkt downregulation.
Conclusion: Overall, resveratrol induced apoptosis in H460 lung cancer cells by specifically targeting pAkt and c-FLIP dowregulation by proteasomal degradation in a EGFR-dependent manner.Export Options
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Cite this article as:
Anti-Tumorigenic Effects of Resveratrol in Lung Cancer Cells Through Modulation of c-FLIP, Current Cancer Drug Targets 2017; 17 (7) . https://dx.doi.org/10.2174/1568009617666170315162932
DOI https://dx.doi.org/10.2174/1568009617666170315162932 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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