JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand
JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand
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DOI：
10.1136/gut.2008.154625
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发表时间：
2009-05-01
期刊：
影响因子：
24.5
通讯作者：
De Toni, E. N.
中科院分区：
文献类型：
--
作者：
Mucha, S. R.;Rizzani, A.;De Toni, E. N.
工作背景：cJun末端激酶（JNK）在大多数肝细胞癌（HCC）中被组成性激活，但其在癌发生中的确切作用仍存在争议。虽然肿瘤坏死因子（TNF）相关的肿瘤坏死诱导配体（TRAIL）被认为是获得性免疫肿瘤监视的主要介质，并且目前正在临床试验中作为新的癌症疗法进行测试，但许多肿瘤对TRAIL的抗性以及对其体内毒性的担忧代表了其临床应用的障碍。在这项研究中，我们调查了肝癌中JNK活性是否有助于这些肿瘤细胞对凋亡的抵抗。方法：通过药理学抑制或RNA干扰分析了JNK/Jun抑制对受体介导的凋亡的影响，这些细胞和非肿瘤细胞分离自人肝脏或缺乏Jun磷酸化位点的转基因小鼠。JNK抑制导致细胞周期停滞，增强caspase募集，并使HCC细胞对TRAIL非常敏感，但对正常肝细胞不敏感。JNK抑制剂SP 600125可有效阻断TRAIL诱导的JNK激活。结论：JNK的表达和依赖于TRAIL的反馈激活可能是癌细胞逃避TRAIL介导的肿瘤监视的机制。JNK抑制可能代表了一种新的策略，特异性致敏肝癌细胞的TRAIL，从而打开了有前途的治疗前景，安全和有效地使用TRAIL在癌症治疗。
Background: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours.Methods: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and nontumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun.Results: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125.Conclusions: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.