Adenoviral vector expressing CYLD augments antitumor activity of TRAIL by suppression of NF-κB survival signaling in hepatocellular carcinoma
Adenoviral vector expressing CYLD augments antitumor activity of TRAIL by suppression of NF-κB survival signaling in hepatocellular carcinoma
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DOI：
10.4161/cbt.5.6.2662
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发表时间：
2006-06-01
影响因子：
3.6
通讯作者：
Liu, Xinyuan
中科院分区：
文献类型：
--
作者：
Chu, Liang;Gu, Jinfa;Liu, Xinyuan
CYLD是与圆柱瘤相关的肿瘤抑制基因，是NF-κ B B的负调节因子。然而，CYLD的抗肿瘤作用尚未见报道。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）诱导的NF-κ B活化使肝细胞癌（hepatocellular carcinoma，HCC）对TRAIL介导的细胞凋亡具有抵抗性。在这里，我们描述了表达CYLD的腺病毒载体（Ad/hTERT-CYLD）通过负调节NF-κ B活性来增强TRAIL在HCC细胞中的细胞毒性，因为CYLD可以逆转TNF受体相关因子2（TRAF 2）的泛素化并与I κ B激酶γ（IKK γ）相互作用。Ad/hTERT-CYLD和携带TRAIL基因的条件复制型腺病毒（ZD 55-TRAIL）联合作用可诱导肝癌细胞快速而有效的凋亡，其特征为caspase-3、caspase-8和PARP的激活以及X连锁凋亡抑制蛋白（XIAP）的减少。在动物实验中，联合治疗可以根除BEL 7404异种移植瘤。相比之下，单独用Ad/hTERT-CYLD或ZD 55-TRAIL治疗获得较少的抗肿瘤效果。结论：CYLD抑制TRAIL介导的NF-κ B B活化，增强肝癌细胞对TRAIL触发的凋亡的敏感性。Ad/hTERT-CYLD和ZD 55-TRAIL的联合递送可能是治疗肝癌或其他NF-κ B活性增强的肿瘤细胞的一种新的有用策略。
CYLD is a tumor suppressor gene related to cylindroma and is negative regulator of NF-kappa B. However, antitumor effect of CYLD has not been reported. The activation of NF-kappa B induced by tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) renders hepatocellular carcinoma (HCC) resistant to TRAIL-mediated cell apoptosis. Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappa B activity since CYLD could reverse the ubiquitination of TNF receptor-associated factor 2 (TRAF2) and interact with the I kappa B kinase gamma (IKK gamma). The combined treatment of Ad/hTERT-CYLD and a conditionally replicating adenovirus carrying TRAIL gene (ZD55-TRAIL) induced rapid and potent apoptosis in HCC cells, characterized by activation of caspase-3, caspase-8, PARP and the reduction of X-linked inhibitor of apoptosis protein ( XIAP). In animal study, the combined treatment could eradicate the BEL7404 xenograft tumors. In contrast, treatment with Ad/hTERT-CYLD or ZD55-TRAIL alone achieved less antitumor effect. In conclusion: CYLD inhibits TRAIL-mediated NF-kappa B activation and enhances the sensitivity of HCC cells to TRAIL-triggered apoptosis. The combined delivery of Ad/hTERT-CYLD and ZD55-TRAIL may be a new useful strategy for HCC or other tumor cells with enhanced NF-kappa B activity.