Resveratrol Induces Premature Senescence in Lung Cancer Cells via ROS-Mediated DNA Damage

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.

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

“…Hydroxyurea, resveratrol, and pyrithione induce premature senescence by ROS generation (Luo et al 2013;Ong et al 2011). Thus, drug targeting premature senescence in cancer cells could be a superior approach rather activating apoptosis because at a lower concentration of the drug, activated senescence regresses the tumor growth by neutralizing the toxicity of the drugs (Wu et al 2007).…”

Anti-tumor effects and cellular mechanisms of resveratrol

“…Some experiments performed on tumor cells revealed two new approaches for p53 and p21 in inducing apoptosis: senescence and autophagy. Resveratrol induced premature senescence was found to be associated with increased expression of p53 and p21 in NSCLC cells (47), suggesting that the activation of the p53-p21 pathway may play an important role in resveratrol induced senescence. The senescence was also found to be related to the increase of NAPDH oxidase-5 (NOX-5)-mediated ROS up-regulation, from which we could suppose that it is the increase of ROS induced p53 and p21 overexpression and resulted in the latter effect: senescence.…”

Catalase Inhibits Ionizing Radiation-Induced Apoptosis in Hematopoietic Stem and Progenitor Cells

“…Phosphorylated H2AX (gH2AX) foci assays were performed to determine DNA double-strand breaks (DSBs) in HSPCs after CAT and/or IR treatments using immunofluorescent microscopic analysis as previously described [10,24]. Briefly, HSPCs were harvested from cultures and cytospun onto slides.…”

“…The protein concentrations were quantified using the Bio-Rad Dc protein assay kit (Bio-Rad Laboratories). Western blotting analysis was performed as previously described [24]. Briefly, 50 mg of protein samples were resolved on 10% Mini-Protean TGX gels (Bio-Rad) and transferred onto 0.2 mM PVDF membrane (Millipore).…”