Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway.
Resveratrol inhibits Extranodal NK/T cell lymphoma through activation of DNA damage response pathway.
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白藜芦醇通过激活 DNA 损伤反应途径抑制结外 NK/T 细胞淋巴瘤
DOI：
10.1186/s13046-017-0601-6
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Yin L
中科院分区：
文献类型：
--
作者：
Sui X;Zhang C;Zhou J;Cao S;Xu C;Tang F;Zhi X;Chen B;Wang S;Yin L
结外NK/T细胞淋巴瘤是一种高度侵袭性的非霍奇金淋巴瘤，预后差。白藜芦醇（Resveratrol，RSV，3，5，4 ′-trihydroxystilbene）是一种存在于葡萄皮和其它种子植物中的天然酚类化合物，具有抗氧化、抗衰老、降低心血管疾病风险和抗癌等多种生物活性。在这里，我们报告了RSV在NKTCL细胞系SNT-8、SNK-10和SNT-16中的抗肿瘤作用。RSV呈剂量和时间依赖性抑制NKTCL细胞增殖，并使细胞周期阻滞于S期。其通过线粒体途径诱导NKTCL细胞凋亡，表现为MCl-1和Survivin表达下调，Bax和Bad表达上调，caspase-9和caspase-3表达激活。另外，我们发现RSV可抑制AKT和Stat 3的磷酸化水平，并直接或通过上调EB病毒（EBV）的Zta激活DNA损伤反应（DDR）通路。进一步以KU 55933为pATM抑制剂，证实DDR在RSV诱导NKTCL凋亡中起重要作用。RSV与足叶乙甙或电离辐射联用对DDR通路的激活也有协同作用，导致细胞增殖抑制和凋亡。我们的研究结果提供了体外证据，RSV通过ATM/Chk 2/p53依赖性方式激活DDR通路产生抗肿瘤作用。因此，我们认为RSV可能是一种值得进一步研究的抗肿瘤药物，用于NKTCL的治疗。本文的在线版本（10.1186/s13046-017-0601-6）包含补充材料，可供授权用户使用。
Extranodal NK/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with poor prognosis. Resveratrol (RSV, 3,5,4′-trihydroxystilbene), a natural nontoxic phenolic compound found in the skin of grapes and some other spermatophytes, performs multiple bioactivities, such as antioxidant activity, anti-aging activity, reduction of cardiovascular disease risk and anticarcinogenic effect. Here we report the anti-tumor effect of RSV in NKTCL cell lines SNT-8, SNK-10 and SNT-16. RSV inhibited NKTCL cell proliferation in a dose- and time-dependent manner and arrested cell cycle at S phase. It induced NKTCL cells apoptosis through mitochondrial pathway, shown as down-regulation of MCl-1 and survivin, up-regulation of Bax and Bad, and activation of caspase-9 and caspase-3. In addition, we found that RSV suppressed the phosphorylation level of AKT and Stat3, and activated DNA damage response (DDR) pathway directly or through up-regulation of Zta of Epstein-Barr virus (EBV). Furthermore, using KU55933 as the inhibitor of pATM, we verified that DDR played an important role in RSV inducing NKTCL apoptosis. RSV also showed synergistic effect on activating DDR pathway in combination with etoposide or ionizing radiation, which resulted in cell proliferation inhibition and apoptosis. Our results provide in vitro evidence that RSV produces anti-tumor effect by activating DDR pathway in an ATM/Chk2/p53 dependent manner. So we suggest that RSV may be worthy for further study as an anti-tumor drug for NKTCL treatment. The online version of this article (10.1186/s13046-017-0601-6) contains supplementary material, which is available to authorized users.
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