17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear Factor-κB pathway
17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear Factor-κB pathway
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DOI：
10.1158/0008-5472.can-05-2698
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Lin, Y
中科院分区：
文献类型：
--
作者：
Wang, X;Ju, W;Lin, Y
核因子-κ B（nuclear factor-kappa B，NTF-kappa B）是肿瘤坏死因子（tumor necrosis factor，TNF）诱导的一种细胞存活信号，在抵抗TNF诱导的细胞死亡中起重要作用。以前的研究表明，热休克蛋白90（Hsp 90）调节受体相互作用蛋白（RIP）和I κ B激酶β（IKK β）的稳定性和功能，这些蛋白是TNF诱导的NF-κ B活化途径的关键组分。在这项研究中，我们发现，热休克蛋白90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17 AAG）与TNF协同诱导肺肿瘤衍生细胞系的细胞凋亡。用17 AAG治疗引起RIP和IKK β降解，这反过来又阻断TNF诱导的NF-κ B活化和抗凋亡基因表达。只有当TNF处理后17 AAG预暴露时才检测到协同细胞毒性。重要的是，在表达不可降解的I κ B α突变体（I κ B α-AA）的NF-κ B失能细胞中，细胞死亡的增强作用被消除。这些结果表明，用17 AAG和TNT处理所观察到的细胞毒性是由阻断TNF诱导的NF-κ B活化引起的。TNF受体I信号级联的其他组分没有改变，而TNF诱导的c-un NH 2-末端激酶活化和凋亡增强。在17 AAG处理的和TNF相关的凋亡诱导配体（TRAIL）处理的癌细胞中也观察到诱导凋亡的类似协同作用。我们的研究结果表明，NF-κ B B在肺癌细胞对TNF和TRAIL的抗性中起关键作用，并且用17 AAG随后用TNF或TRAIL治疗来使这种存活抑制失效可能是肺癌的有效的新治疗策略。
Nuclear factor-kappa B (NTF-kappa B), a survival signal induced by tumor necrosis factor (TNF), contributes substantially to the resistarice to TNF-induced cell death. Previous studies suggest that heat shock protein 90 (Hsp90) regulates the stability and function of receptor-interaction proteins (RIP) and I kappa B kinase beta (IKK beta), the key components of the TNF-induced NF-kappa B activation pathway. In this study, we showed that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) was synergistic with TNF to induce apoptotic cell death in a panel of lung tumor-derived cell lines. Treatment with 17AAG caused degradation of RIP and IKK beta that, in turn, blocked TNF-induced NF-kappa B activation and antiapoptotic gene expression. The synergistic cytotoxicity was detected only when TNF treatment followed 17AAG preexposure. Importantly, the potentiation of cell death was abolished in NF-kappa B-disabled cells that express a nondegradable I kappa B alpha mutant (I kappa B alpha-AA). These results suggest that the cytotoxicity seen with 17AAG and TNT treatment results from blocking TNF-induced NF-kappa B activation. The other components of the TNF receptor I signaling cascade were not altered, whereas TNF-induced c-] un NH2-terminal kinase activation and apoptosis were potentiated. A similar synergism for inducing apoptosis was also observed in 17AAG-treated and TNF-related apoptosis-inducing ligand (TRAIL)-treated cancer cells. Our results suggest that NF-kappa B plays a key role in the resistance of lung cancer cells to TNF and TRAIL and that disabling this survival si;Mal with 17AAG followed by TNF or TRAIL treatment could be an effective new therapeutic strategy for lung cancer.