Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage.
Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage.
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DOI：
10.1371/journal.pone.0060065
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang GY
中科院分区：
文献类型：
--
作者：
Luo H;Yang A;Schulte BA;Wargovich MJ;Wang GY
白藜芦醇(RV)是红葡萄酒和葡萄中的一种天然成分，已被证明是一种潜在的化学预防和抗癌药物。然而，RV的抗癌和化学预防作用的分子机制还不完全清楚。在这里，我们显示RV治疗以剂量依赖的方式抑制非小细胞肺癌(NSCLC)细胞的克隆生长。有趣的是，低剂量RV的抑瘤作用与裂解的PARP和激活的caspase-3的表达没有明显变化相关，提示低剂量RV治疗可能通过非细胞凋亡机制抑制肿瘤细胞的生长。随后的研究表明，低剂量RV治疗可显著增加非小细胞肺癌细胞衰老相关β-半乳糖苷酶(SA-β-GAL)的表达，并上调P53和p21的表达。此外，我们发现RV诱导的对肺癌细胞生长的抑制与EF1a表达的减少有关。这些结果提示，RV可能通过诱导早衰而发挥其抗癌和化学预防作用。从机制上讲，RV诱导的早衰与肺癌细胞DNA双链断裂(DSB)和活性氧(ROS)的产生增加有关。N-乙酰半胱氨酸(NAC)抑制ROS的产生可减轻RV诱导的DNA双链断裂和早衰。此外，我们发现RV处理显著地诱导了A549和H460细胞中NAPDH氧化酶-5(Nox5)的表达，这表明RV可能通过上调Nox5的表达来增加肺癌细胞中ROS的生成。总之，这些发现表明，低剂量RV治疗通过一种以前未被认识的机制抑制肺癌细胞的生长，即通过ROS介导的DNA损伤诱导过早衰老。
Resveratrol (RV) is a natural component of red wine and grapes that has been shown to be a potential chemopreventive and anticancer agent. However, the molecular mechanisms underlying RV's anticancer and chemopreventive effects are incompletely understood. Here we show that RV treatment inhibits the clonogenic growth of non-small cell lung cancer (NSCLC) cells in a dose-dependent manner. Interestingly, the tumor-suppressive effect of low dose RV was not associated with any significant changes in the expression of cleaved PARP and activated caspase-3, suggesting that low dose RV treatment may suppress tumor cell growth via an apoptosis-independent mechanism. Subsequent studies reveal that low dose RV treatment induces a significant increase in senescence-associated β–galactosidase (SA-β-gal) staining and elevated expression of p53 and p21 in NSCLC cells. Furthermore, we show that RV-induced suppression of lung cancer cell growth is associated with a decrease in the expression of EF1A. These results suggest that RV may exert its anticancer and chemopreventive effects through the induction of premature senescence. Mechanistically, RV-induced premature senescence correlates with increased DNA double strand breaks (DSBs) and reactive oxygen species (ROS) production in lung cancer cells. Inhibition of ROS production by N-acetylcysteine (NAC) attenuates RV-induced DNA DSBs and premature senescence. Furthermore, we show that RV treatment markedly induces NAPDH oxidase-5 (Nox5) expression in both A549 and H460 cells, suggesting that RV may increase ROS generation in lung cancer cells through upregulating Nox5 expression. Together, these findings demonstrate that low dose RV treatment inhibits lung cancer cell growth via a previously unappreciated mechanism, namely the induction of premature senescence through ROS-mediated DNA damage.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
3.5
作者：
Ami, AS;Bhat, SH;Hadi, SM
通讯作者：
Hadi, SM
影响因子：
3.7
作者：
Hussain AR;Uddin S;Bu R;Khan OS;Ahmed SO;Ahmed M;Al-Kuraya KS
通讯作者：
Al-Kuraya KS
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J