Aspirin sensitizes cancer cells to TRAIL-Induced apoptosis by reducing survivin levels
Aspirin sensitizes cancer cells to TRAIL-Induced apoptosis by reducing survivin levels
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DOI：
10.1158/1078-0432.ccr-07-4362
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Cryns, Vincent L.
中科院分区：
文献类型：
--
作者：
Lu, Meiling;Strohecker, Anne;Cryns, Vincent L.
目的：尽管肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 和针对其受体的激动性抗体由于其肿瘤选择性而成为有前景的癌症治疗方法，但许多肿瘤对基于 TRAIL 的疗法具有耐药性。我们在体外和体内检查了非甾体类抗炎药物阿司匹林是否使癌细胞对 TRAIL 激动剂敏感，并研究了其潜在机制。 实验设计：在人乳腺癌细胞系和异种移植肿瘤中确定阿司匹林对 TRAIL 激动剂敏感性和凋亡调节剂表达的影响。通过沉默 survivin 来确定 survivin 耗竭在阿司匹林 TRAIL 敏化作用中的具体作用。 结果：阿司匹林通过不依赖环氧合酶 2 的机制使人乳腺癌细胞（而非未转化的人乳腺上皮细胞）对 TRAIL 诱导的 caspase 激活和细胞凋亡敏感。阿司匹林还能使乳腺癌细胞对人激动性 TRAIL 受体 2 单克隆抗体 (lexatumumab) 诱导的细胞凋亡敏感。阿司匹林治疗导致G细胞周期停滞，并通过诱导蛋白酶体降解，导致抗凋亡蛋白生存素的水平大幅降低，但不影响许多其他凋亡调节因子的水平。用小干扰RNA沉默生存素可使乳腺癌细胞对TRAIL诱导的细胞凋亡敏感，这强调了生存素耗竭在阿司匹林的TRAIL敏化作用中的功能作用。此外，阿司匹林与 TRAIL 协同作用，在原位乳腺癌异种移植模型中促进细胞凋亡并减轻肿瘤负荷。结论：阿司匹林通过一种涉及生存素耗竭的新机制，在体外和体内使转化的乳腺上皮细胞对基于 TRAIL 的疗法敏感。这些发现为该组合的治疗效用提供了第一个体内证据。
Purpose: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism.Experimental Design: The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin.Results: Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G, cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model.Conclusions: Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.