Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells
Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in...
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| description | Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in NRF2 liberation and accumulation in the nucleus. In the present study, we aimed to investigate the effect of KEAP1 knockdown on NRF2 target gene expression and its toxicological implication using human colon cancer cells. The stable KEAP1-knockdown HT29 cells exhibit elevated levels of NRF2 and its target gene expressions. In particular, the mRNA levels of aldo-keto reductases (AKR1C1, 1C2, 1C3, 1B1, and 1B10) were substantially increased in KEAP1 silenced HT29 cells. These differential AKRs expressions appear to contribute to protection against oxidative stress. The KEAP1-knockdown cells were relatively more resistant to hydrogen peroxide (H2O2) and 4-hydroxynonenal (4HNE) compared to the control cells. Accordantly, we observed accumulation of 4HNE protein adducts in H2O2- or 4HNE-treated control cells, whereas KEAP1-knockdown cells did not increase adduct formation. The treatment of KEAP1-silenced cells with AKR1C inhibitor flufenamic acid increased 4HNE-induced cellular toxicity and protein adduct formation. Taken together, these results indicate that AKRs, which are NRF2-dependent highly inducible gene clusters, play a role in NRF2-mediated cytoprotection against lipid peroxide toxicity. |
| doi_str_mv | 10.1155/2013/423965 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3674683</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>23766854</sourcerecordid><originalsourceid>FETCH-LOGICAL-c401t-744218b8311cee8cb937e5cab211bd73daed78994aa53bc43feb43a053b98b553</originalsourceid><addsrcrecordid>eNqFkElPwzAQhS0EolA4cQblDAq1YzvLBamKCkVUKmI5W7YzoUapU8Ut0H-PQyCCE5dZNN-80TyETgi-JITzUYQJHbGIZjHfQQckY1GIs4zt9jXGA3To3CvGMY0Y2UeDiCZxnHJ2gOYTu5BWQxGwcLotmvpja2sLVlbBAzjj1u0wMDa4m4zvSfBoKviip5ultEFeV7WPLdMEOVSVO0J7pawcHH_nIXq-njzl03A2v7nNx7NQM0zWYcJYRFKVUkI0QKpVRhPgWqqIEFUktJBQJKn_QkpOlWa0BMWoxL7JUsU5HaKrTne1UUsoNNh1IyuxasxSNltRSyP-TqxZiJf6TdA4YXFKvcBFJ6Cb2rkGyn6XYNH6KlpfReerp89-n-vZHyM9cN4BC2ML-W7-UTvtYPAIlLKHWUKwf-4TWE6Jtw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central Open Access</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Jung, Kyeong-Ah ; Kwak, Mi-Kyoung</creator><contributor>Pi, Jingbo</contributor><creatorcontrib>Jung, Kyeong-Ah ; Kwak, Mi-Kyoung ; Pi, Jingbo</creatorcontrib><description>Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in NRF2 liberation and accumulation in the nucleus. In the present study, we aimed to investigate the effect of KEAP1 knockdown on NRF2 target gene expression and its toxicological implication using human colon cancer cells. The stable KEAP1-knockdown HT29 cells exhibit elevated levels of NRF2 and its target gene expressions. In particular, the mRNA levels of aldo-keto reductases (AKR1C1, 1C2, 1C3, 1B1, and 1B10) were substantially increased in KEAP1 silenced HT29 cells. These differential AKRs expressions appear to contribute to protection against oxidative stress. The KEAP1-knockdown cells were relatively more resistant to hydrogen peroxide (H2O2) and 4-hydroxynonenal (4HNE) compared to the control cells. Accordantly, we observed accumulation of 4HNE protein adducts in H2O2- or 4HNE-treated control cells, whereas KEAP1-knockdown cells did not increase adduct formation. The treatment of KEAP1-silenced cells with AKR1C inhibitor flufenamic acid increased 4HNE-induced cellular toxicity and protein adduct formation. Taken together, these results indicate that AKRs, which are NRF2-dependent highly inducible gene clusters, play a role in NRF2-mediated cytoprotection against lipid peroxide toxicity.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2013/423965</identifier><identifier>PMID: 23766854</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Puplishing Corporation</publisher><subject>Aldehyde Reductase - metabolism ; Aldehydes - metabolism ; Aldo-Keto Reductases ; Cell Death - drug effects ; Cell Survival - drug effects ; Cell Survival - genetics ; Colonic Neoplasms - genetics ; Colonic Neoplasms - pathology ; DNA Adducts - metabolism ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockdown Techniques ; Gene Silencing - drug effects ; HCT116 Cells ; HEK293 Cells ; HT29 Cells ; Humans ; Hydrogen Peroxide - pharmacology ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - metabolism ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 - metabolism ; Oxidative Stress - drug effects ; Oxidative Stress - genetics ; Vitamin K 3 - pharmacology</subject><ispartof>Oxidative medicine and cellular longevity, 2013-01, Vol.2013 (2013), p.1-16</ispartof><rights>Copyright © 2013 Kyeong-Ah Jung and Mi-Kyoung Kwak.</rights><rights>Copyright © 2013 K.-A. Jung and M.-K. Kwak. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c401t-744218b8311cee8cb937e5cab211bd73daed78994aa53bc43feb43a053b98b553</citedby><cites>FETCH-LOGICAL-c401t-744218b8311cee8cb937e5cab211bd73daed78994aa53bc43feb43a053b98b553</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/PMC3674683/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674683/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23766854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pi, Jingbo</contributor><creatorcontrib>Jung, Kyeong-Ah</creatorcontrib><creatorcontrib>Kwak, Mi-Kyoung</creatorcontrib><title>Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in NRF2 liberation and accumulation in the nucleus. In the present study, we aimed to investigate the effect of KEAP1 knockdown on NRF2 target gene expression and its toxicological implication using human colon cancer cells. The stable KEAP1-knockdown HT29 cells exhibit elevated levels of NRF2 and its target gene expressions. In particular, the mRNA levels of aldo-keto reductases (AKR1C1, 1C2, 1C3, 1B1, and 1B10) were substantially increased in KEAP1 silenced HT29 cells. These differential AKRs expressions appear to contribute to protection against oxidative stress. The KEAP1-knockdown cells were relatively more resistant to hydrogen peroxide (H2O2) and 4-hydroxynonenal (4HNE) compared to the control cells. Accordantly, we observed accumulation of 4HNE protein adducts in H2O2- or 4HNE-treated control cells, whereas KEAP1-knockdown cells did not increase adduct formation. The treatment of KEAP1-silenced cells with AKR1C inhibitor flufenamic acid increased 4HNE-induced cellular toxicity and protein adduct formation. Taken together, these results indicate that AKRs, which are NRF2-dependent highly inducible gene clusters, play a role in NRF2-mediated cytoprotection against lipid peroxide toxicity.</description><subject>Aldehyde Reductase - metabolism</subject><subject>Aldehydes - metabolism</subject><subject>Aldo-Keto Reductases</subject><subject>Cell Death - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - genetics</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - pathology</subject><subject>DNA Adducts - metabolism</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>Gene Silencing - drug effects</subject><subject>HCT116 Cells</subject><subject>HEK293 Cells</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kelch-Like ECH-Associated Protein 1</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - genetics</subject><subject>Vitamin K 3 - pharmacology</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><recordid>eNqFkElPwzAQhS0EolA4cQblDAq1YzvLBamKCkVUKmI5W7YzoUapU8Ut0H-PQyCCE5dZNN-80TyETgi-JITzUYQJHbGIZjHfQQckY1GIs4zt9jXGA3To3CvGMY0Y2UeDiCZxnHJ2gOYTu5BWQxGwcLotmvpja2sLVlbBAzjj1u0wMDa4m4zvSfBoKviip5ultEFeV7WPLdMEOVSVO0J7pawcHH_nIXq-njzl03A2v7nNx7NQM0zWYcJYRFKVUkI0QKpVRhPgWqqIEFUktJBQJKn_QkpOlWa0BMWoxL7JUsU5HaKrTne1UUsoNNh1IyuxasxSNltRSyP-TqxZiJf6TdA4YXFKvcBFJ6Cb2rkGyn6XYNH6KlpfReerp89-n-vZHyM9cN4BC2ML-W7-UTvtYPAIlLKHWUKwf-4TWE6Jtw</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Jung, Kyeong-Ah</creator><creator>Kwak, Mi-Kyoung</creator><general>Hindawi Puplishing Corporation</general><general>Hindawi Publishing Corporation</general><scope>AACQA</scope><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</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>5PM</scope></search><sort><creationdate>20130101</creationdate><title>Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells</title><author>Jung, Kyeong-Ah ; Kwak, Mi-Kyoung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c401t-744218b8311cee8cb937e5cab211bd73daed78994aa53bc43feb43a053b98b553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aldehyde Reductase - metabolism</topic><topic>Aldehydes - metabolism</topic><topic>Aldo-Keto Reductases</topic><topic>Cell Death - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - genetics</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colonic Neoplasms - pathology</topic><topic>DNA Adducts - metabolism</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Knockdown Techniques</topic><topic>Gene Silencing - drug effects</topic><topic>HCT116 Cells</topic><topic>HEK293 Cells</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kelch-Like ECH-Associated Protein 1</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - genetics</topic><topic>Vitamin K 3 - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, Kyeong-Ah</creatorcontrib><creatorcontrib>Kwak, Mi-Kyoung</creatorcontrib><collection>بنك معلومات "معرفة" لدراسات العلوم العسكرية والأمنية - e-Marefa Military & Security Database</collection><collection>الدوريات العلمية والإحصائية - e-Marefa Academic and Statistical Periodicals</collection><collection>معرفة - المحتوى العربي الأكاديمي المتكامل - e-Marefa Academic Complete</collection><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oxidative medicine and cellular longevity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jung, Kyeong-Ah</au><au>Kwak, Mi-Kyoung</au><au>Pi, Jingbo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells</atitle><jtitle>Oxidative medicine and cellular longevity</jtitle><addtitle>Oxid Med Cell Longev</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>2013</volume><issue>2013</issue><spage>1</spage><epage>16</epage><pages>1-16</pages><issn>1942-0900</issn><eissn>1942-0994</eissn><abstract>Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in NRF2 liberation and accumulation in the nucleus. In the present study, we aimed to investigate the effect of KEAP1 knockdown on NRF2 target gene expression and its toxicological implication using human colon cancer cells. The stable KEAP1-knockdown HT29 cells exhibit elevated levels of NRF2 and its target gene expressions. In particular, the mRNA levels of aldo-keto reductases (AKR1C1, 1C2, 1C3, 1B1, and 1B10) were substantially increased in KEAP1 silenced HT29 cells. These differential AKRs expressions appear to contribute to protection against oxidative stress. The KEAP1-knockdown cells were relatively more resistant to hydrogen peroxide (H2O2) and 4-hydroxynonenal (4HNE) compared to the control cells. Accordantly, we observed accumulation of 4HNE protein adducts in H2O2- or 4HNE-treated control cells, whereas KEAP1-knockdown cells did not increase adduct formation. The treatment of KEAP1-silenced cells with AKR1C inhibitor flufenamic acid increased 4HNE-induced cellular toxicity and protein adduct formation. Taken together, these results indicate that AKRs, which are NRF2-dependent highly inducible gene clusters, play a role in NRF2-mediated cytoprotection against lipid peroxide toxicity.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Puplishing Corporation</pub><pmid>23766854</pmid><doi>10.1155/2013/423965</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Oxidative medicine and cellular longevity, 2013-01, Vol.2013 (2013), p.1-16 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Wiley Online Library (Open Access Collection); PubMed Central; Alma/SFX Local Collection |
| subjects | Aldehyde Reductase - metabolism Aldehydes - metabolism Aldo-Keto Reductases Cell Death - drug effects Cell Survival - drug effects Cell Survival - genetics Colonic Neoplasms - genetics Colonic Neoplasms - pathology DNA Adducts - metabolism Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Gene Silencing - drug effects HCT116 Cells HEK293 Cells HT29 Cells Humans Hydrogen Peroxide - pharmacology Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 - metabolism Oxidative Stress - drug effects Oxidative Stress - genetics Vitamin K 3 - pharmacology |
| title | Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells |
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