Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines
Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines
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DOI：
10.1053/jhep.2000.16266
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发表时间：
2000-09-01
期刊：
影响因子：
13.5
通讯作者：
Suzuki, A
中科院分区：
文献类型：
--
作者：
Yamanaka, T;Shiraki, K;Suzuki, A
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性地诱导各种转化细胞系的凋亡，但在几乎正常的组织中不诱导凋亡。它受2种死亡受体（TRAIL受体1（TRAIL-R1）和TRAIL-R2）以及2种诱饵受体（TRAIL-R3和TRAIL-R4）调节。我们研究了人肝细胞癌（HCC）中TRAIL-R和TRAIL诱导的凋亡的表达。TRAIL-R1、-R2和-R4在6个检测的HCC细胞系中表达，但TRAIL-R3仅在2个细胞系中表达。此外，免疫组化结果显示TRAIL-R1和TRAIL-R2在人HCC组织中的高表达和普遍表达。尽管表达TRAIL-R1和-R2，但所有6种肝癌细胞系均显示对TRAIL诱导的凋亡的抵抗，而与TRAIL诱导的核因子-κ B（NF-κ B）水平无关。TRAIL诱导的死亡信号被抑制，caspase-8和caspase-3活性均降低。然而，TRAIL诱导显着的细胞凋亡中存在的亚毒性水平的放线菌素D，表明TRAIL诱导的细胞凋亡途径是在这些细胞系。此外，我们发现，治疗与传统的化疗药物，阿霉素和喜树碱，显着增强TRAIL诱导的细胞毒性，在大多数的肝癌细胞系。放线菌素D和喜树碱几乎完全抑制了TRAIL对NF-κ B的诱导，而多柔比星的作用很小。这些结果表明，TRAIL，与化疗药物组合，可能有治疗人类肝癌的治疗潜力。
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2, and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. We investigated the expression of TRAIL-R- and TRAIL-induced apoptosis in human hepatocellular carcinomas (HCCs). TRAIL R1, -R2, and -R4 were expressed in 6 HCC cell lines examined, but TRAIL-R3 was expressed in only 2 of the 6 cell lines. In addition, immunohistochemical results revealed a high and prevalent expression of TRAIL-R1 and -R2 in human HCC tissues. Despite the expression of TRAIL-R1 and -R2, all 6 HCC cell lines showed resistance to TRAIL-induced apoptosis with no relation to nuclear factor kappa B (NF-kappa B) levels induced by TRAIL. TRAIL-induced death signal was inhibited with both decreased caspase-8 and caspase-3 activity. However, TRAIL induced significant apoptosis in the presence of a subtoxic level of actinomycin D, indicating that the TRAIL-induced apoptotic pathway is in place in these cell lines. In addition, we found that treatment with conventional chemotherapeutic agents, doxorubicin and camptothecin, dramatically augmented TRAIL-induced cytotoxicity in most of the HCC cell lines. Actinomycin D and camptothecin almost completely suppressed NF-kappa B induction by TRAIL, whereas doxorubicin had little effect. These results indicate that TRAIL, in combination with chemotherapeutic agents, may have therapeutic potential in the treatment of human HCC.