Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage
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 inhibit...
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description | 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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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0060065</identifier><identifier>PMID: 23533664</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylcysteine ; Anticancer properties ; Apoptosis ; Biology ; Blotting, Western ; Cancer ; Cancer cells ; Cancer genetics ; Cancer prevention ; Cancer therapies ; Cancer treatment ; Caspase ; Caspase-3 ; Cell cycle ; Cell Line, Tumor ; Cellular Senescence - drug effects ; Chemotherapy ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA Damage - drug effects ; Drug dosages ; Fibroblasts ; Flow Cytometry ; Galactosidase ; Grapes ; Humans ; Ionizing radiation ; Laboratories ; Lung cancer ; Lung diseases ; Lung Neoplasms - genetics ; Medical prognosis ; Medicine ; Molecular modelling ; NAD(P)H oxidase ; Non-small cell lung cancer ; Non-small cell lung carcinoma ; Oxidative stress ; Oxygen ; p53 Protein ; Pathology ; Poly(ADP-ribose) polymerase ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Respiratory system agents ; Resveratrol ; Reverse Transcriptase Polymerase Chain Reaction ; Senescence ; Stilbenes - pharmacology ; Tumor proteins ; Wine ; Wines ; β-Galactosidase</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e60065</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Luo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Luo et al 2013 Luo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-d612b6a3c61ce80da13eadc7feac3471ecb8517a70dcfa84e452a83d60f4e27a3</citedby><cites>FETCH-LOGICAL-c692t-d612b6a3c61ce80da13eadc7feac3471ecb8517a70dcfa84e452a83d60f4e27a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606183/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606183/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23871,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23533664$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahmad, Aamir</contributor><creatorcontrib>Luo, Hongmei</creatorcontrib><creatorcontrib>Yang, Aimin</creatorcontrib><creatorcontrib>Schulte, Bradley A</creatorcontrib><creatorcontrib>Wargovich, Michael J</creatorcontrib><creatorcontrib>Wang, Gavin Y</creatorcontrib><title>Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Acetylcysteine</subject><subject>Anticancer properties</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer genetics</subject><subject>Cancer prevention</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Caspase</subject><subject>Caspase-3</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cellular Senescence - drug effects</subject><subject>Chemotherapy</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Damage - drug effects</subject><subject>Drug dosages</subject><subject>Fibroblasts</subject><subject>Flow Cytometry</subject><subject>Galactosidase</subject><subject>Grapes</subject><subject>Humans</subject><subject>Ionizing radiation</subject><subject>Laboratories</subject><subject>Lung cancer</subject><subject>Lung diseases</subject><subject>Lung Neoplasms - genetics</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Molecular modelling</subject><subject>NAD(P)H oxidase</subject><subject>Non-small cell lung cancer</subject><subject>Non-small cell lung carcinoma</subject><subject>Oxidative stress</subject><subject>Oxygen</subject><subject>p53 Protein</subject><subject>Pathology</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Respiratory system agents</subject><subject>Resveratrol</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Senescence</subject><subject>Stilbenes - pharmacology</subject><subject>Tumor proteins</subject><subject>Wine</subject><subject>Wines</subject><subject>β-Galactosidase</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2LEzEYhQdR3A_9B6IDguBFazKZyaQ3C2X9KiwWuip4Fd4m70xTMpOazJT135va2aUDCpJAvp73JDmcJHlByZSykr7but63YKc71-KUEB578Sg5pzOWTXhG2OOT-VlyEcKWkIIJzp8mZxkrGOM8P09-rDDs0UPnnU1Nq3uFId15bKDrPaYBWwwKW4XxMLV9W6cK4sqnCq0N6d5AulreThrUBjrU6fsv81RDAzU-S55UYAM-H8bL5NvHD1-vP09ulp8W1_ObieKzrJtoTrM1B6Y4VSiIBsoQtCorBMXykqJai4KWUBKtKhA55kUGgmlOqhyzEthl8uqou7MuyMGVICljRMwoy2aRWBwJ7WArd9404H9JB0b-2XC-luA7oyzKqlivuVCcA4Fcl1QoraiAEkglqjI_3HY13Nav46ejNZ0HOxIdn7RmI2u3l4wTTgWLAq8HAe9-9hi6fzx5oGqIrzJt5aKYakxQcp6XgvKiyA9a079QsWlsjIq5qEzcHxW8HRVEpsO7roY-BLm4Xf0_u_w-Zt-csBsE222Cs31nXBvGYH4ElXcheKwenKNEHmJ974Y8xFoOsY5lL09dfyi6zzH7DSQ2834</recordid><startdate>20130322</startdate><enddate>20130322</enddate><creator>Luo, Hongmei</creator><creator>Yang, Aimin</creator><creator>Schulte, Bradley A</creator><creator>Wargovich, Michael J</creator><creator>Wang, Gavin Y</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130322</creationdate><title>Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage</title><author>Luo, Hongmei ; Yang, Aimin ; Schulte, Bradley A ; Wargovich, Michael J ; Wang, Gavin Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-d612b6a3c61ce80da13eadc7feac3471ecb8517a70dcfa84e452a83d60f4e27a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acetylcysteine</topic><topic>Anticancer properties</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer genetics</topic><topic>Cancer prevention</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Caspase</topic><topic>Caspase-3</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cellular Senescence - drug effects</topic><topic>Chemotherapy</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Damage - drug effects</topic><topic>Drug dosages</topic><topic>Fibroblasts</topic><topic>Flow Cytometry</topic><topic>Galactosidase</topic><topic>Grapes</topic><topic>Humans</topic><topic>Ionizing radiation</topic><topic>Laboratories</topic><topic>Lung cancer</topic><topic>Lung diseases</topic><topic>Lung Neoplasms - genetics</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Molecular modelling</topic><topic>NAD(P)H oxidase</topic><topic>Non-small cell lung cancer</topic><topic>Non-small cell lung carcinoma</topic><topic>Oxidative stress</topic><topic>Oxygen</topic><topic>p53 Protein</topic><topic>Pathology</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Respiratory system agents</topic><topic>Resveratrol</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Senescence</topic><topic>Stilbenes - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23533664</pmid><doi>10.1371/journal.pone.0060065</doi><oa>free_for_read</oa></addata></record> |
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subjects | Acetylcysteine Anticancer properties Apoptosis Biology Blotting, Western Cancer Cancer cells Cancer genetics Cancer prevention Cancer therapies Cancer treatment Caspase Caspase-3 Cell cycle Cell Line, Tumor Cellular Senescence - drug effects Chemotherapy Deoxyribonucleic acid DNA DNA damage DNA Damage - drug effects Drug dosages Fibroblasts Flow Cytometry Galactosidase Grapes Humans Ionizing radiation Laboratories Lung cancer Lung diseases Lung Neoplasms - genetics Medical prognosis Medicine Molecular modelling NAD(P)H oxidase Non-small cell lung cancer Non-small cell lung carcinoma Oxidative stress Oxygen p53 Protein Pathology Poly(ADP-ribose) polymerase Reactive oxygen species Reactive Oxygen Species - metabolism Respiratory system agents Resveratrol Reverse Transcriptase Polymerase Chain Reaction Senescence Stilbenes - pharmacology Tumor proteins Wine Wines β-Galactosidase |
title | Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T19%3A15%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Resveratrol%20induces%20premature%20senescence%20in%20lung%20cancer%20cells%20via%20ROS-mediated%20DNA%20damage&rft.jtitle=PloS%20one&rft.au=Luo,%20Hongmei&rft.date=2013-03-22&rft.volume=8&rft.issue=3&rft.spage=e60065&rft.pages=e60065-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0060065&rft_dat=%3Cgale_plos_%3EA478165543%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1330891329&rft_id=info:pmid/23533664&rft_galeid=A478165543&rft_doaj_id=oai_doaj_org_article_f5bb68c66a0a4d718cdc18a7a0f8f74a&rfr_iscdi=true |