Luteolin sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis
Luteolin sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis
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DOI：
10.1016/j.lfs.2014.02.002
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发表时间：
2014-04-01
期刊：
影响因子：
6.1
通讯作者：
Chen, Chun-Jung
中科院分区：
文献类型：
--
作者：
Ou, Yen-Chuan;Li, Jian-Ri;Chen, Chun-Jung
目的：肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）被认为是治疗包括肾细胞癌（renal cell carcinoma，RCC）在内的多种肿瘤的最有希望的候选药物之一。然而，许多细胞对TRAIL诱导的凋亡具有抗性，这限制了TRAIL在癌症治疗中的潜在应用。木犀草素是一种天然存在的黄酮类化合物，由于其强大的癌细胞杀伤活性，已被确定为潜在的癌症治疗和预防剂。在这项研究中，我们研究了毛地黄黄酮治疗是否可以调节肾癌中TRAIL诱导的细胞凋亡。主要方法：在人RCC 786-O、ACHN和A498细胞中评估毛地黄黄酮对TRAIL敏感性的影响。潜在的监管级联接近生化和药理学strategies.Key发现：我们发现，单独的无毒浓度的木樨草素没有影响细胞凋亡的水平，但联合治疗的TRAIL和木樨草素引起显着的外在和内在的细胞凋亡。这种致敏作用伴随着Bid裂解、Mcl-1和FLIP下调、DR 4/DR 5蛋白表达和细胞表面呈递以及Akt和信号转导和转录激活因子3（STAT 3）失活。在这些现象中，FLIP、Akt和STAT 3的变化更容易受到毛地黄黄酮治疗的影响。研究进一步表明，单独的Ala或STAT 3的失活足以下调FLIP的表达，并使786-0细胞对TRAIL诱导的apoptosis.Significance敏感：因此，本研究的数据提供了体外证据，支持毛地黄黄酮是TRAIL在涉及Alct和STAT 3失活的抗人RCC的抗癌治疗中的潜在致敏剂的观点。(c)2014爱思唯尔公司All rights reserved.
Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered to be one of the most promising candidates in research on treatments for cancer, including renal cell carcinoma (RCC). However, many cells are resistant to TRAIL-induced apoptosis which limits the potential application of TRAIL in cancer therapy. Luteolin, a naturally occurring flavonoid, has been identified as a potential therapeutic and preventive agent for cancer because of its potent cancer cell-killing activity. In this study, we investigated whether luteolin treatment could modulate TRAIL-induced apoptosis in RCC.Main methods: The effect of luteolin on TRAIL sensitivity was assessed in human RCC 786-O, ACHN, and A498 cells. The underlying regulatory cascades were approached by biochemical and pharmacological strategies.Key findings: We found that nontoxic concentration of luteolin alone had no effect on the level of apoptosis, but a combination treatment of TRAIL and luteolin caused significant extrinsic and intrinsic apoptosis. The sensitization was accompanied by Bid cleavage, Mcl-1 and FLIP down-regulation, DR4/DR5 protein expression and cell surface presentation, and Akt and signal transducer and activator of transcription-3 (STAT3) inactivation. Among these phenomena, changes in FLIP, Akt, and, STAT3 are more prone to the effects of luteolin treatment. Studies have further demonstrated that inactivation of Ala or STAT3 alone was sufficient to down-regulate FLIP expression and sensitized 786-0 cells to TRAIL-induced apoptosis.Significance: Data from this study thus provide in vitro evidence supporting the notion that luteolin is a potential sensitizer of TRAIL in anticancer therapy against human RCC involving Alct and STAT3 inactivation. (c) 2014 Elsevier Inc. All rights reserved.