Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways
Pemetrexed, a new‐generation antifolate, has demonstrated promising single‐agent activity in front‐ and second‐line treatments of non‐small cell lung cancer. However, the molecular mechanism of pemetrexed‐mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DN...
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| Veröffentlicht in: | Molecular carcinogenesis 2013-03, Vol.52 (3), p.183-194 |
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| container_title | Molecular carcinogenesis |
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| creator | Yang, Tsung-Ying Chang, Gee-Chen Chen, Kun-Chieh Hung, Hsiao-Wen Hsu, Kuo-Hsuan Wu, Chi-Hao Sheu, Gwo-Tarng Hsu, Shih-Lan |
| description | Pemetrexed, a new‐generation antifolate, has demonstrated promising single‐agent activity in front‐ and second‐line treatments of non‐small cell lung cancer. However, the molecular mechanism of pemetrexed‐mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DNA damage and caspase‐2, ‐3, ‐8, and ‐9 activation in A549 cells and that treatment with caspase inhibitors significantly abolished cell death, suggesting a caspase‐dependent apoptotic mechanism. The molecular events of pemetrexed‐mediated apoptosis was associated with the activation of ataxia telangiectasia mutated (ATM)/p53‐dependent and ‐independent signaling pathways, which promoted intrinsic and extrinsic apoptosis by upregulating Bax, PUMA, Fas, DR4, and DR5 and activating the caspase signaling cascade. Supplementation with dTTP allowed normal S‐phase progression and rescued apoptotic death in response to pemetrexed. Overall, our findings reveal that the decrease of thymidylate synthase and the increase of Bax, PUMA, Fas, DR4, and DR5 genes may serve as biomarkers for predicting responsiveness to pemetrexed. © 2011 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/mc.21842 |
| format | Article |
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However, the molecular mechanism of pemetrexed‐mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DNA damage and caspase‐2, ‐3, ‐8, and ‐9 activation in A549 cells and that treatment with caspase inhibitors significantly abolished cell death, suggesting a caspase‐dependent apoptotic mechanism. The molecular events of pemetrexed‐mediated apoptosis was associated with the activation of ataxia telangiectasia mutated (ATM)/p53‐dependent and ‐independent signaling pathways, which promoted intrinsic and extrinsic apoptosis by upregulating Bax, PUMA, Fas, DR4, and DR5 and activating the caspase signaling cascade. Supplementation with dTTP allowed normal S‐phase progression and rescued apoptotic death in response to pemetrexed. Overall, our findings reveal that the decrease of thymidylate synthase and the increase of Bax, PUMA, Fas, DR4, and DR5 genes may serve as biomarkers for predicting responsiveness to pemetrexed. © 2011 Wiley Periodicals, Inc.</description><identifier>ISSN: 0899-1987</identifier><identifier>EISSN: 1098-2744</identifier><identifier>DOI: 10.1002/mc.21842</identifier><identifier>PMID: 22086658</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Antimetabolites, Antineoplastic - pharmacology ; Apoptosis ; Apoptosis - drug effects ; ataxia telangiectasia mutated ; Ataxia Telangiectasia Mutated Proteins ; Cancer therapies ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Caspases - metabolism ; Cell Cycle Proteins - metabolism ; Cell Line, Tumor ; DNA Damage - drug effects ; DNA-Binding Proteins - metabolism ; Enzyme Activation - drug effects ; Enzymes ; Glutamates - pharmacology ; Guanine - analogs & derivatives ; Guanine - pharmacology ; Humans ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mutation ; p53 ; Pemetrexed ; Protein-Serine-Threonine Kinases - metabolism ; PUMA ; S Phase Cell Cycle Checkpoints - drug effects ; Signal Transduction - drug effects ; Thymine Nucleotides - pharmacology ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Molecular carcinogenesis, 2013-03, Vol.52 (3), p.183-194</ispartof><rights>Copyright © 2011 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4532-dbfc65e766a146b3d39733b2c5726b8b9dd0e35f9affbff21e5e602ff46f327d3</citedby><cites>FETCH-LOGICAL-c4532-dbfc65e766a146b3d39733b2c5726b8b9dd0e35f9affbff21e5e602ff46f327d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmc.21842$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmc.21842$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22086658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Tsung-Ying</creatorcontrib><creatorcontrib>Chang, Gee-Chen</creatorcontrib><creatorcontrib>Chen, Kun-Chieh</creatorcontrib><creatorcontrib>Hung, Hsiao-Wen</creatorcontrib><creatorcontrib>Hsu, Kuo-Hsuan</creatorcontrib><creatorcontrib>Wu, Chi-Hao</creatorcontrib><creatorcontrib>Sheu, Gwo-Tarng</creatorcontrib><creatorcontrib>Hsu, Shih-Lan</creatorcontrib><title>Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways</title><title>Molecular carcinogenesis</title><addtitle>Mol. Carcinog</addtitle><description>Pemetrexed, a new‐generation antifolate, has demonstrated promising single‐agent activity in front‐ and second‐line treatments of non‐small cell lung cancer. However, the molecular mechanism of pemetrexed‐mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DNA damage and caspase‐2, ‐3, ‐8, and ‐9 activation in A549 cells and that treatment with caspase inhibitors significantly abolished cell death, suggesting a caspase‐dependent apoptotic mechanism. The molecular events of pemetrexed‐mediated apoptosis was associated with the activation of ataxia telangiectasia mutated (ATM)/p53‐dependent and ‐independent signaling pathways, which promoted intrinsic and extrinsic apoptosis by upregulating Bax, PUMA, Fas, DR4, and DR5 and activating the caspase signaling cascade. Supplementation with dTTP allowed normal S‐phase progression and rescued apoptotic death in response to pemetrexed. Overall, our findings reveal that the decrease of thymidylate synthase and the increase of Bax, PUMA, Fas, DR4, and DR5 genes may serve as biomarkers for predicting responsiveness to pemetrexed. © 2011 Wiley Periodicals, Inc.</description><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>ataxia telangiectasia mutated</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Cancer therapies</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Caspases - metabolism</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>DNA Damage - drug effects</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzymes</subject><subject>Glutamates - pharmacology</subject><subject>Guanine - analogs & derivatives</subject><subject>Guanine - pharmacology</subject><subject>Humans</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mutation</subject><subject>p53</subject><subject>Pemetrexed</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>PUMA</subject><subject>S Phase Cell Cycle Checkpoints - drug effects</subject><subject>Signal Transduction - drug effects</subject><subject>Thymine Nucleotides - pharmacology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0899-1987</issn><issn>1098-2744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kV1rFDEUhoModq2Cv0AGvPFm2nxMkplLWbQKbS1WEbwJmeRkN3W-mmTo7s_wH5u22y0UvApveHiSc16E3hJ8RDCmx705oqSu6DO0ILipSyqr6jla4LppStLU8gC9ivEKY0Ikxy_RAaW4FoLXC_T3AnpIATZgCz_Y2UAs2jGtc0jBD9GbQg-2gM0-TeOUxuhjkdZhnFfrQie98bpI0Olh5cEkHXPs56QT2OOJs9LCBIOFId25yvzO_iL61aA7P6yKSaf1jd7G1-iF012EN7vzEP38_OnH8kt5-u3k6_LjaWkqzmhpW2cEBymEJpVomWWNZKylhksq2rptrMXAuGu0c61zlAAHgalzlXCMSssO0Yd77xTG6xliUr2PBro8BYxzVITmhdaCcJLR90_Qq3EO-d-Zqqq88aam4lFowhhjAKem4HsdtopgdVuT6o26qymj73bCue3B7sGHXjJQ3gM3voPtf0XqbPkg3PE-JtjseR3-KCGZ5OrX-YkSlxfL8--_L1XF_gFeta2s</recordid><startdate>201303</startdate><enddate>201303</enddate><creator>Yang, Tsung-Ying</creator><creator>Chang, Gee-Chen</creator><creator>Chen, Kun-Chieh</creator><creator>Hung, Hsiao-Wen</creator><creator>Hsu, Kuo-Hsuan</creator><creator>Wu, Chi-Hao</creator><creator>Sheu, Gwo-Tarng</creator><creator>Hsu, Shih-Lan</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><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>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201303</creationdate><title>Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways</title><author>Yang, Tsung-Ying ; Chang, Gee-Chen ; Chen, Kun-Chieh ; Hung, Hsiao-Wen ; Hsu, Kuo-Hsuan ; Wu, Chi-Hao ; Sheu, Gwo-Tarng ; Hsu, Shih-Lan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4532-dbfc65e766a146b3d39733b2c5726b8b9dd0e35f9affbff21e5e602ff46f327d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>ataxia telangiectasia mutated</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Cancer therapies</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Caspases - metabolism</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Line, Tumor</topic><topic>DNA Damage - drug effects</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzymes</topic><topic>Glutamates - pharmacology</topic><topic>Guanine - analogs & derivatives</topic><topic>Guanine - pharmacology</topic><topic>Humans</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mutation</topic><topic>p53</topic><topic>Pemetrexed</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>PUMA</topic><topic>S Phase Cell Cycle Checkpoints - drug effects</topic><topic>Signal Transduction - drug effects</topic><topic>Thymine Nucleotides - pharmacology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Tsung-Ying</creatorcontrib><creatorcontrib>Chang, Gee-Chen</creatorcontrib><creatorcontrib>Chen, Kun-Chieh</creatorcontrib><creatorcontrib>Hung, Hsiao-Wen</creatorcontrib><creatorcontrib>Hsu, Kuo-Hsuan</creatorcontrib><creatorcontrib>Wu, Chi-Hao</creatorcontrib><creatorcontrib>Sheu, Gwo-Tarng</creatorcontrib><creatorcontrib>Hsu, Shih-Lan</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular carcinogenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Tsung-Ying</au><au>Chang, Gee-Chen</au><au>Chen, Kun-Chieh</au><au>Hung, Hsiao-Wen</au><au>Hsu, Kuo-Hsuan</au><au>Wu, Chi-Hao</au><au>Sheu, Gwo-Tarng</au><au>Hsu, Shih-Lan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways</atitle><jtitle>Molecular carcinogenesis</jtitle><addtitle>Mol. Carcinog</addtitle><date>2013-03</date><risdate>2013</risdate><volume>52</volume><issue>3</issue><spage>183</spage><epage>194</epage><pages>183-194</pages><issn>0899-1987</issn><eissn>1098-2744</eissn><abstract>Pemetrexed, a new‐generation antifolate, has demonstrated promising single‐agent activity in front‐ and second‐line treatments of non‐small cell lung cancer. However, the molecular mechanism of pemetrexed‐mediated antitumor activity remains unclear. The current study shows that pemetrexed induced DNA damage and caspase‐2, ‐3, ‐8, and ‐9 activation in A549 cells and that treatment with caspase inhibitors significantly abolished cell death, suggesting a caspase‐dependent apoptotic mechanism. The molecular events of pemetrexed‐mediated apoptosis was associated with the activation of ataxia telangiectasia mutated (ATM)/p53‐dependent and ‐independent signaling pathways, which promoted intrinsic and extrinsic apoptosis by upregulating Bax, PUMA, Fas, DR4, and DR5 and activating the caspase signaling cascade. Supplementation with dTTP allowed normal S‐phase progression and rescued apoptotic death in response to pemetrexed. Overall, our findings reveal that the decrease of thymidylate synthase and the increase of Bax, PUMA, Fas, DR4, and DR5 genes may serve as biomarkers for predicting responsiveness to pemetrexed. © 2011 Wiley Periodicals, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>22086658</pmid><doi>10.1002/mc.21842</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Molecular carcinogenesis, 2013-03, Vol.52 (3), p.183-194 |
| issn | 0899-1987 1098-2744 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Antimetabolites, Antineoplastic - pharmacology Apoptosis Apoptosis - drug effects ataxia telangiectasia mutated Ataxia Telangiectasia Mutated Proteins Cancer therapies Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Caspases - metabolism Cell Cycle Proteins - metabolism Cell Line, Tumor DNA Damage - drug effects DNA-Binding Proteins - metabolism Enzyme Activation - drug effects Enzymes Glutamates - pharmacology Guanine - analogs & derivatives Guanine - pharmacology Humans Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Mutation p53 Pemetrexed Protein-Serine-Threonine Kinases - metabolism PUMA S Phase Cell Cycle Checkpoints - drug effects Signal Transduction - drug effects Thymine Nucleotides - pharmacology Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism |
| title | Pemetrexed induces both intrinsic and extrinsic apoptosis through ataxia telangiectasia mutated/p53-dependent and -independent signaling pathways |
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