Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells
Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells
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DOI：
10.1093/carcin/bgm133
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发表时间：
2007-10-01
期刊：
影响因子：
4.7
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
Chen, Wenshu;Wang, Xia;Lin, Yong
流行病学研究表明，天然黄酮类化合物槲皮素具有预防肺癌的活性;然而，其机制尚未得到很好的阐明。在这份报告中，我们证明，槲皮素显着增强肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞毒性在非小细胞肺癌（NSCLC）细胞。槲皮素增加死亡受体（DR）5的表达，而它对死亡诱导信号复合物的其他成分没有影响。相反，槲皮素有效抑制生存素的表达。我们进一步确定，蛋白激酶C（PKC）是必不可少的DR 5诱导，但抑制生存素的表达。相反，槲皮素对丝氨酸/苏氨酸激酶Akt活性的阻断对于抑制生存素表达而不是诱导DR 5是重要的。这些结果表明槲皮素调控DR 5和Survivin表达的途径是不同的。重要的是，抑制存活素致敏的TRAIL诱导的细胞死亡和阻断DR 5表达抑制了槲皮素和TRAIL共处理诱导的协同细胞毒性。总的来说，我们的数据表明，槲皮素敏化TRAIL诱导的细胞毒性在肺癌细胞通过两个独立的途径：诱导DR 5和抑制生存素的表达，这可能是槲皮素的肺癌预防活性的机制。增强TRAIL诱导的NSCLC细胞死亡可能与肺癌的治疗和预防有关。
The natural flavonoid quercetin has been suggested by epidemiological studies to have preventive activity against lung cancer; however, the mechanism of which has not been well elucidated. In this report, we demonstrate that quercetin significantly enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells. Quercetin increased expression of death receptor (DR) 5, whereas it had no effect on that of other components of the death-inducing signaling complex. Conversely, the expression of survivin was potently inhibited by quercetin. We further determined that Protein Kinase C (PKC) is essential for DR5 induction but is dispensable for suppression of survivin expression. In contrast, the blockage of the serine/threonine kinase Akt activity by quercetin is important for inhibition of survivin expression but not induction of DR5. These results suggest the pathways for regulation of DR5 and survivin expression by quercetin are distinct. Importantly, suppression of survivin-sensitized TRAIL-induced cell death and blockage of DR5 expression suppressed the synergistic cytotoxicity induced by quercetin and TRAIL co-treatment. On the whole, our data show that quercetin sensitizes TRAIL-induced cytotoxicity in lung cancer cells through two independent pathways: induction of DR5 and suppression of survivin expression, which may underlie the mechanism of the lung cancer preventive activity of quercetin. The potentiation of TRAIL-induced NSCLC cell death could be implicated in lung cancer therapy and prevention.