新型HSP90抑制剂抗胃癌作用及机制研究高通量筛选eIF4E抑制剂及其抗肿瘤作用研究
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摘要
热休克蛋白90(Hsp90)是一种广泛存在于细胞中的分子伴侣(molecular chaperone)。它通过稳定肿瘤细胞中的原癌蛋白(例如Akt和c-Raf)从而参与多种细胞内信号转导过程。Hsp90抑制剂17-AAG在临床试验中展现出颇具希望的抗肿瘤效应,但由于其潜在的毒性和不良的药代特性,进一步的应用受到限制。因此现阶段的努力集中于开发具有更强药效和更低副作用的新型Hsp90抑制剂。本研究利用荧光偏振竞争结合实验筛选了百余种小分子化合物,并筛选出一种作用较强的间苯二酚衍生物LD053,它能与Hsp90ATP结合口袋有效地结合。LD053与Hsp90的结合能将辅分子伴侣cdc37从Hsp90上解离下来,导致Akt和c-Raf的不稳定,并通过提高泛素化而使两者降解,进而抑制下游的PI3K/Akt和c-Raf/Mek/Erk信号通路。结果,LD053降低了BGC8231中瘤细胞的活力并诱导其凋亡,表现为细胞在subGO/G1期的积累,同时cleaved-caspase3和PARP的增多。但正常细胞对LD053并不敏感。与体外抗肿瘤活性一致,LD053能显著抑制裸鼠体内BGC823异种移植瘤的生长,而体重却未见明显降低。以上结果均表明,LD053是一种新型的Hsp90抑制剂,并具有潜力用于胃癌的治疗。
近期研究表明,由eIF4F复合物起始的帽依赖的翻译过程对多种原癌蛋白的表达是必需的,这些原癌蛋白包括c-Myc, survivin, Cyclin D1, Mcl-1, VEGF等。因此帽依赖的翻译在人类肿瘤中常常是处于上调的状态。作为eIF4F复合物的重要组成部分,真核生物翻译起始因子4E (eIF4E)是帽依赖翻译的限速因子,并且经常因为基因扩增和转录上调而在肿瘤细胞中过表达。siRNA或反义寡核苷酸引起的eIF4E的表达下调能够有效地抑制肿瘤细胞的生长并诱导凋亡,而且没有明显毒性。这些结果使研究者们对开发新型的小分子药物产生了浓厚的兴趣,这些小分子药物能靶向于eIF4E区动的翻译起始装置。基于FRT介导的同源重组,本实验室建立了一种基于荧光素酶报告体的检测方法,能够高通量地筛选抑制eIF4E表达的小分子化合物。应用该方法我们筛选了NCI Diversity-Set化合物库,筛选出一个小分子,代号为48F10,它能在较低的微摩尔浓度显著地抑制几种乳腺癌细胞eIF4E的mRNA表达,进而剂量和时间依赖性地降低HS578T细胞中eIF4E的蛋白水平,导致下游蛋白survivin, cyclin D1, Mcl-1和c-myc的下调,同时抑制乳腺癌细胞的生长,并诱导凋亡,表现为cleaved-caspase3和cleaved-PARP的明显增多。因此,48F10代表了一类新的eIF4E抑制剂,能通过抑制eIF4E的转录而抑制帽依赖的翻译。
Heat shock protein90(Hsp90) is a molecular chaperone engaging in multiple cellular signaling by stabilizing oncoproteins (e.g., Akt and c-Raf) in tumor cells. Whereas Hsp90inhibitors such as17-AAG exert promising antitumor effects in clinical trials, current efforts focus on developing agents targeting Hsp90with improved efficacy and lower toxicity. Using a fluorescence polarization assay, over a hundred of synthetic small molecules were screened and a resorcinol derivative LD053that bound the Hsp90ATP-binding pocket effectively was identified. The binding of LD053to Hsp90dissociated the co-chaperone protein cdc37from Hsp90, resulting in destabilization of Akt and c-Raf and subsequent inhibition of PI3K/Akt and c-Raf/Mek/Erk signaling in BGC823gastric cancer cells. As a consequence, LD053decreased cancer cell viability and induced apoptosis evidenced by increased subGO/G1cell population and increased cleavage of caspase3and PARP. Interestingly, normal human cells appeared insensitive to LD053treatments. Consistent with its in vitro anticancer activities, LD053significantly inhibited growth of BGC823xenografts in nude mice without apparent body weight loss. These results thus demonstrate that LD053is a novel Hsp90inhibitor and has potential to be used to treat gastric cancer.
Recent studies have demonstrated that cap-dependent translation initiated by the eIF4F complex is required for expression of a variety of oncogenic proteins including c-Myc, survivin, Cyclin D1, Mcl-1, VEGF. It is thus not surprising that cap-dependent translation is often elevated in human cancers. As a major component of the eIF4F initiation complex, eukaryotic translation initiation factor4E (eIF4E) is the rate-limiting factor for cap-dependent translation initiation and frequently overexpressed in cancers due to gene amplification and transcriptional upregulation. Down-regulation of eIF4E expression by siRNA or anti-sense oligonucleotides was shown to inhibit cancer cell growth and promote apoptosis without apparent toxicity. These results have generated increasing interests in the discovery of novel molecules targeting eIF4E-driven translation-initiation apparatus. Based on FRT-mediated homologous recombination, we developed a luciferase-based reporter assay that can be used to screen for small molecules inhibitory for eIF4E expression in a high-throughput manner. We screened the NCI Diversity-Set chemical library, and identified a small molecule, referred to as48F10, that significantly decreased the eIF4E mRNA level at lower micromolar concentrations in several kinds of breast cancer cells. As a consequence, this small molecule decreased the eIF4E protein level dose dependently, leading to reduced expression of survivin, cyclin D1, Mcl-1and c-Myc. Moreover, we found that this novel eIF4E inhibitor inhibited breast cancer cell growth and induced apoptosis sharply evidenced by increased cleavage of caspase3and PARP.48F10thus represents a novel class of eIF4E inhibitors that suppress cap-dependent translation through inhibiting eIF4E expression.
近期研究表明,由eIF4F复合物起始的帽依赖的翻译过程对多种原癌蛋白的表达是必需的,这些原癌蛋白包括c-Myc, survivin, Cyclin D1, Mcl-1, VEGF等。因此帽依赖的翻译在人类肿瘤中常常是处于上调的状态。作为eIF4F复合物的重要组成部分,真核生物翻译起始因子4E (eIF4E)是帽依赖翻译的限速因子,并且经常因为基因扩增和转录上调而在肿瘤细胞中过表达。siRNA或反义寡核苷酸引起的eIF4E的表达下调能够有效地抑制肿瘤细胞的生长并诱导凋亡,而且没有明显毒性。这些结果使研究者们对开发新型的小分子药物产生了浓厚的兴趣,这些小分子药物能靶向于eIF4E区动的翻译起始装置。基于FRT介导的同源重组,本实验室建立了一种基于荧光素酶报告体的检测方法,能够高通量地筛选抑制eIF4E表达的小分子化合物。应用该方法我们筛选了NCI Diversity-Set化合物库,筛选出一个小分子,代号为48F10,它能在较低的微摩尔浓度显著地抑制几种乳腺癌细胞eIF4E的mRNA表达,进而剂量和时间依赖性地降低HS578T细胞中eIF4E的蛋白水平,导致下游蛋白survivin, cyclin D1, Mcl-1和c-myc的下调,同时抑制乳腺癌细胞的生长,并诱导凋亡,表现为cleaved-caspase3和cleaved-PARP的明显增多。因此,48F10代表了一类新的eIF4E抑制剂,能通过抑制eIF4E的转录而抑制帽依赖的翻译。
Heat shock protein90(Hsp90) is a molecular chaperone engaging in multiple cellular signaling by stabilizing oncoproteins (e.g., Akt and c-Raf) in tumor cells. Whereas Hsp90inhibitors such as17-AAG exert promising antitumor effects in clinical trials, current efforts focus on developing agents targeting Hsp90with improved efficacy and lower toxicity. Using a fluorescence polarization assay, over a hundred of synthetic small molecules were screened and a resorcinol derivative LD053that bound the Hsp90ATP-binding pocket effectively was identified. The binding of LD053to Hsp90dissociated the co-chaperone protein cdc37from Hsp90, resulting in destabilization of Akt and c-Raf and subsequent inhibition of PI3K/Akt and c-Raf/Mek/Erk signaling in BGC823gastric cancer cells. As a consequence, LD053decreased cancer cell viability and induced apoptosis evidenced by increased subGO/G1cell population and increased cleavage of caspase3and PARP. Interestingly, normal human cells appeared insensitive to LD053treatments. Consistent with its in vitro anticancer activities, LD053significantly inhibited growth of BGC823xenografts in nude mice without apparent body weight loss. These results thus demonstrate that LD053is a novel Hsp90inhibitor and has potential to be used to treat gastric cancer.
Recent studies have demonstrated that cap-dependent translation initiated by the eIF4F complex is required for expression of a variety of oncogenic proteins including c-Myc, survivin, Cyclin D1, Mcl-1, VEGF. It is thus not surprising that cap-dependent translation is often elevated in human cancers. As a major component of the eIF4F initiation complex, eukaryotic translation initiation factor4E (eIF4E) is the rate-limiting factor for cap-dependent translation initiation and frequently overexpressed in cancers due to gene amplification and transcriptional upregulation. Down-regulation of eIF4E expression by siRNA or anti-sense oligonucleotides was shown to inhibit cancer cell growth and promote apoptosis without apparent toxicity. These results have generated increasing interests in the discovery of novel molecules targeting eIF4E-driven translation-initiation apparatus. Based on FRT-mediated homologous recombination, we developed a luciferase-based reporter assay that can be used to screen for small molecules inhibitory for eIF4E expression in a high-throughput manner. We screened the NCI Diversity-Set chemical library, and identified a small molecule, referred to as48F10, that significantly decreased the eIF4E mRNA level at lower micromolar concentrations in several kinds of breast cancer cells. As a consequence, this small molecule decreased the eIF4E protein level dose dependently, leading to reduced expression of survivin, cyclin D1, Mcl-1and c-Myc. Moreover, we found that this novel eIF4E inhibitor inhibited breast cancer cell growth and induced apoptosis sharply evidenced by increased cleavage of caspase3and PARP.48F10thus represents a novel class of eIF4E inhibitors that suppress cap-dependent translation through inhibiting eIF4E expression.
引文
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