Abstract
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.
Highlights
Lung cancer is responsible for more cancer deaths in the United States than the combined mortality of colorectal, breast and prostate cancer [1]
We show that low dose RV treatment leads to a significant increase in senescence-associated b–galactosidase (SA-b-gal) staining and elevated p53 and p21 expression in non-small cell lung cancer (NSCLC) cells, suggesting that the anticancer effect of RV is largely attributable to the induction of senescence in lung cancer cells
Previous studies have indicated that higher doses of RV treatment may inhibit the proliferation of tumor cells by inducing apoptosis [28,29,30,31], but a major challenge for this apoptosis-causing strategy is that the concentration required to induce apoptosis in tumor cells in vitro is not reachable in vivo [5,6,7,32]
Summary
Lung cancer is responsible for more cancer deaths in the United States than the combined mortality of colorectal, breast and prostate cancer [1]. Even with the newer advanced therapeutic approaches, the 5-year overall survival rate is less than 16% and has not changed appreciably over many decades [1,2]. This poor prognosis emphasizes the urgent need for the development of novel strategies for the prevention and more effective treatment of this deadly disease. The use of NPs as antitumor agents for the management of human cancers is an attractive idea because they are readily available and exhibit little or no toxicity [3,5,6,7]. The goal of this study was to define the role of premature senescence in RV-induced antitumor effects in lung cancer cells
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