Sensitization for tumor necrosis factor-related apoptosis-inducing ligand induced apoptosis by the chemopreventive agent resveratrol
Sensitization for tumor necrosis factor-related apoptosis-inducing ligand induced apoptosis by the chemopreventive agent resveratrol
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DOI：
10.1158/0008-5472.can-03-1656
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发表时间：
2004-01-01
期刊：
影响因子：
11.2
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Fulda, S;Debatin, KM
存活素是凋亡抑制蛋白的成员，其在大多数人类癌症中以高水平表达并且可促进逃避凋亡和异常有丝分裂进展。天然存在的膳食化合物如白藜芦醇作为癌症化学预防剂已经获得了相当大的关注。在这里，我们发现了一个新的功能的化学预防剂白藜芦醇：白藜芦醇是一个潜在的敏化剂的肿瘤细胞的肿瘤坏死因子相关的凋亡诱导配体（TRAIL）诱导的凋亡，通过p53非依赖性诱导或p21和p21介导的细胞周期阻滞与生存素耗尽。细胞周期，生存素表达和细胞凋亡的伴随分析显示，白藜芦醇诱导的G1阻滞与生存素表达的下调和TRAIL诱导的细胞凋亡的敏化有关。因此，使用细胞周期抑制剂含羞草碱或由p21过表达诱导的G1阻滞降低了存活素表达并使细胞对TRAIL处理敏感。同样，白藜芦醇介导的细胞周期停滞，随后生存素耗尽和敏感的TRAIL在p21缺陷细胞受损。此外，使用生存素反义寡核苷酸下调生存素使细胞对TRAIL诱导的凋亡敏感。重要的是，白藜芦醇敏化各种肿瘤细胞系，但不是正常的人成纤维细胞，死亡受体连接或抗癌药物诱导的细胞凋亡。因此，这种组合的敏化剂（白藜芦醇）/诱导剂（例如，TRAIL）策略可能是增强基于TRAIL的疗法在多种人类癌症中的功效的新方法。
Survivin is a member of the inhibitor of apoptosis proteins that is expressed at high levels in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Naturally occurring dietary compounds such as resveratrol have gained considerable attention as cancer chemopreventive agents. Here, we discovered a novel function of the chemopreventive agent resveratrol: resveratrol is a potent-sensitizer of tumor cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through p53-independent induction or p21 and p21-mediated cell cycle arrest associated with survivin depletion. Concomitant analysis of cell cycle, survivin expression, and apoptosis revealed that resveratrol-induced G, arrest was associated with down-regulation of survivin expression and sensitization for TRAIL-induced apoptosis. Accordingly, G, arrest using the cell cycle inhibitor mimosine or induced by p21 overexpression reduced survivin expression and sensitized cells for TRAIL treatment. Likewise, resveratrol-mediated cell cycle arrest followed by survivin depletion and sensitization for TRAIL was impaired in p21-deficient cells. Also, down-regulation of survivin using survivin antisense oligonucleotides sensitized cells for TRAIL-induced apoptosis. Importantly, resveratrol sensitized various tumor cell lines, but not normal human fibroblasts, for apoptosis induced by death receptor ligation or anticancer drugs. Thus, this combined sensitizer (resveratrol)/ inducer (e.g., TRAIL) strategy may be a novel approach to enhance the efficacy of TRAIL-based therapies in a variety of human cancers.