Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL
Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL
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DOI：
10.1002/hep.20807
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发表时间：
2005-09-01
期刊：
影响因子：
13.5
通讯作者：
Walczak, H
中科院分区：
文献类型：
--
作者：
Ganten, TM;Koschny, R;Walczak, H
TRAIL在小鼠全身给药时表现出有效的抗肿瘤活性。由于其在体内的有效性，TRAIL可能作为一种新的抗肿瘤药物。然而，迄今为止测试的肿瘤细胞系中约有一半是TRAIL抗性的，并且已经描述了某些重组形式的TRAIL对人肝细胞的潜在毒副作用。用蛋白酶体抑制剂MG 132和PS-341预处理使TRAIL耐药的肝细胞癌（HCC）细胞系对TRAIL诱导的凋亡敏感，但对原代人肝细胞不敏感。我们研究了不同水平的MG 132诱导的抗凋亡信号转导干扰。尽管蛋白酶体抑制有效地抑制了核因子-κ B（NF-κ B）活性，但mut kappa B α对NF-κ B的特异性抑制未能使TRAIL抗性细胞系对TRAIL诱导的凋亡敏感。与先前报道的5-氟尿嘧啶（5-FU）致敏机制相反，蛋白酶体抑制剂预处理可显著上调TRAIL死亡诱导信号复合物（DISC）中的细胞FLICE抑制蛋白（cFLIP）（L）和cFLIP（S）。与5-FU预处理相比，在MG 132预处理的细胞中，尽管DISC中存在较少的死亡受体和较多的cFLIP，但caspase-8更有效地募集到DISC中。但是通过短干扰RNA（siRNA）下调cFLIP进一步使HCC细胞系敏感。总之，这些结果表明，在存在高水平cFLIP的情况下，其他化疗抗性肿瘤细胞可以在DISC水平上对TRAIL诱导的细胞凋亡敏感，这表明存在调节FADD和TRAIL死亡受体相互作用的额外因子。具有临床意义的是，蛋白酶体抑制剂使肝癌细胞而不是原代人肝细胞对TRAIL诱导的细胞凋亡敏感。
TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-kappa B) activity, specific suppression of NF-kappa B by mut kappa B alpha failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)(L) and cFLIP(S) were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC., But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis.