Lipoxygenase inhibitors induce death receptor 5/TRAIL‐R2 expression and sensitize malignant tumor cells to TRAIL‐induced apoptosis
Lipoxygenase inhibitors induce death receptor 5/TRAIL‐R2 expression and sensitize malignant tumor cells to TRAIL‐induced apoptosis
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DOI：
10.1111/j.1349-7006.2007.00559.x
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发表时间：
2007-09
期刊：
影响因子：
5.7
通讯作者：
Tatsushi Yoshida;T. Shiraishi;Mano Horinaka;Susumu Nakata;Takashi Yasuda;A. Goda;Miki Wakada;Y. Mizutani;T. Miki;A. Nishikawa;T. Sakai
中科院分区：
文献类型：
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作者：
Tatsushi Yoshida;T. Shiraishi;Mano Horinaka;Susumu Nakata;Takashi Yasuda;A. Goda;Miki Wakada;Y. Mizutani;T. Miki;A. Nishikawa;T. Sakai
脂氧合酶诱导恶性肿瘤进展，脂氧合酶抑制剂被认为是有前途的抗肿瘤药物。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是新的癌症治疗方法中最有前途的候选者之一。去甲二氢愈创木酸（NDGA），一种脂氧合酶抑制剂，和TRAIL的联合治疗显着诱导Jurkat T细胞白血病细胞在每种药物的次优浓度的凋亡。联合治疗有效地激活了caspase-3、-8和-10以及Bid。研究NDGA增强TRAIL诱导的细胞凋亡的潜在机制。NDGA未改变抗凋亡因子Bcl-xL、Bcl-2、cIAP-1、XIAP和Survivin的表达水平。研究了死亡受体相关基因的表达，发现NDGA在mRNA和蛋白水平特异性上调死亡受体5（DR 5）的表达。通过小干扰RNA下调DR 5阻止了NDGA对TRAIL诱导的细胞凋亡的增敏作用。此外，NDGA使前列腺癌和结直肠癌细胞对TRAIL诱导的凋亡敏感。相比之下，NDGA既不增强TRAIL诱导的凋亡，也不上调正常外周血单核细胞中DR 5的表达。另一种脂氧合酶抑制剂AA 861也上调DR 5，并使Jurkat和DU 145细胞对TRAIL敏感。这些结果表明，脂氧合酶抑制剂通过在恶性肿瘤细胞中上调DR 5来增加TRAIL的凋亡效率，并提高了脂氧合酶抑制剂和TRAIL的组合是恶性肿瘤治疗的有希望的策略的可能性。（Cancer Sci 2007; 98：1417-1423）
Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti‐tumor agents. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T‐cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase‐3, ‐8 and ‐10, and Bid. The underling mechanism by which NDGA enhanced TRAIL‐induced apoptosis was examined. NDGA did not change the expression levels of anti‐apoptotic factors, Bcl‐xL, Bcl‐2, cIAP‐1, XIAP and survivin. The expression of death receptor‐related genes was investigated and it was found that NDGA specifically up‐regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down‐regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL‐induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL‐induced apoptosis. In contrast, NDGA neither enhanced TRAIL‐induced apoptosis nor up‐regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up‐regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up‐regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment. (Cancer Sci 2007; 98: 1417–1423)