A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1
The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the...
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| Veröffentlicht in: | PloS one 2014-09, Vol.9 (9), p.e107204-e107204 |
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| creator | Han, Bo Li, Wei Sun, Yulin Zhou, Lanping Xu, Yang Zhao, Xiaohang |
| description | The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis. |
| doi_str_mv | 10.1371/journal.pone.0107204 |
| format | Article |
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Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107204</identifier><identifier>PMID: 25232961</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Antioxidants ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Arsenic ; Autophagy ; Autophagy - drug effects ; Biology and Life Sciences ; BNIP3 protein ; Breast cancer ; Cancer ; Cancer genetics ; Carcinoma, Squamous Cell - drug therapy ; Caspase ; Cell cycle ; Cell Cycle Proteins - biosynthesis ; Cell Cycle Proteins - genetics ; Cell death ; Cell growth ; Cell Line, Tumor ; Cell Membrane Permeability - drug effects ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Cytometry ; Cytotoxicity ; Esophageal cancer ; Esophageal Neoplasms - drug therapy ; Esophageal Squamous Cell Carcinoma ; Esophagus ; Flow cytometry ; Gene expression ; Genes ; Humans ; Hydroxybenzoates - pharmacology ; Hydroxylase ; Hypoxia ; Hypoxia-inducible factors ; Immunoglobulins ; Intracellular Signaling Peptides and Proteins - biosynthesis ; Intracellular Signaling Peptides and Proteins - genetics ; Laboratories ; Life sciences ; Medicine and Health Sciences ; Membrane Proteins - biosynthesis ; Metabolism ; Metastases ; Microtubule-associated protein 1 ; Mitochondria ; Mitochondrial Membranes - physiology ; Myc protein ; Oncology ; Phagocytosis ; Polyphenols ; Prolyl-Hydroxylase Inhibitors - pharmacology ; Proteins ; Proto-Oncogene Proteins - biosynthesis ; Protocatechuic acid ; Regulators ; Resveratrol ; RNA Interference ; RNA, Small Interfering ; S phase ; S Phase Cell Cycle Checkpoints - drug effects ; Seeds ; Signaling ; siRNA ; Squamous cell carcinoma ; Studies ; Up-regulation</subject><ispartof>PloS one, 2014-09, Vol.9 (9), p.e107204-e107204</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Han et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Han et al 2014 Han et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c622t-771ea403a0bbb59bc8adea0e7cafd320bdf1397b00721408c9cc71a263e98b7b3</citedby><cites>FETCH-LOGICAL-c622t-771ea403a0bbb59bc8adea0e7cafd320bdf1397b00721408c9cc71a263e98b7b3</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/PMC4169646/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169646/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25232961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sarkar, Devanand</contributor><creatorcontrib>Han, Bo</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Sun, Yulin</creatorcontrib><creatorcontrib>Zhou, Lanping</creatorcontrib><creatorcontrib>Xu, Yang</creatorcontrib><creatorcontrib>Zhao, Xiaohang</creatorcontrib><title>A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.</description><subject>Analysis</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Arsenic</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biology and Life Sciences</subject><subject>BNIP3 protein</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Caspase</subject><subject>Cell cycle</subject><subject>Cell Cycle Proteins - biosynthesis</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cytometry</subject><subject>Cytotoxicity</subject><subject>Esophageal cancer</subject><subject>Esophageal Neoplasms - drug therapy</subject><subject>Esophageal Squamous Cell Carcinoma</subject><subject>Esophagus</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Humans</subject><subject>Hydroxybenzoates - pharmacology</subject><subject>Hydroxylase</subject><subject>Hypoxia</subject><subject>Hypoxia-inducible factors</subject><subject>Immunoglobulins</subject><subject>Intracellular Signaling Peptides and Proteins - biosynthesis</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Laboratories</subject><subject>Life sciences</subject><subject>Medicine and Health Sciences</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Metabolism</subject><subject>Metastases</subject><subject>Microtubule-associated protein 1</subject><subject>Mitochondria</subject><subject>Mitochondrial Membranes - physiology</subject><subject>Myc protein</subject><subject>Oncology</subject><subject>Phagocytosis</subject><subject>Polyphenols</subject><subject>Prolyl-Hydroxylase Inhibitors - pharmacology</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - biosynthesis</subject><subject>Protocatechuic acid</subject><subject>Regulators</subject><subject>Resveratrol</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>S phase</subject><subject>S Phase Cell Cycle Checkpoints - drug effects</subject><subject>Seeds</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Squamous cell carcinoma</subject><subject>Studies</subject><subject>Up-regulation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</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>eNqNk9tu1DAQhiMEolB4AwSWkBBIzWLHOd4glYrDSlWLON1aE3uSdZXEqe2ULg_JM-HdplUX9QLlIrHn-3_Hc4iiZ4wuGC_Y2zMz2QG6xWgGXFBGi4Sm96JHrOJJnCeU37_1vRc9du6M0oyXef4w2kuyhCdVzh5Ffw7JaE237uLVWllzue7AIdHDStfaG3tA0K9CkB-ksdIzUuPw24DHg8CpSaIjEruOwOTNuIJ2TWBQBEYzeuO0CxBBt40gdMSdT9CbadZIsFIPpoft0pELDWQaY4vt1IHXZiCmIe9Pll_41vQk7teSKPNrcN4i9NcgKtLigDF7Ej1ooHP4dH7vRz8-fvh-9Dk-Pv20PDo8jmWeJD4uCoaQUg60ruusqmUJCoFiIaFRPKG1ahivipqGrLKUlrKSsmCQ5Byrsi5qvh-9uPIdO-PEXAonWJZzmpZFRQOxvCKUgTMxWt2DXQsDWmw3jG0FWK9lhwKZxCwDVasiT1ld1hlrEgRAxjgoSIPXu_m0qe5RSRy8hW7HdDcy6JVozYVIWV7laR4MXs8G1pxP6LzotdtkHAYMtdj-d1WWBUsC-vIf9O7bzVQL4QJ6aEw4V25MxWHKSsbLLCsCtbiDCo_CXsvQt40O-zuCNzuCwHi89C1Mzonlt6__z57-3GVf3WJXoQ_9yplu2nSY2wXTK1Ba45zF5ibJjIrN2F1nQ2zGTsxjF2TPbxfoRnQ9Z_wvLxgtCw</recordid><startdate>20140918</startdate><enddate>20140918</enddate><creator>Han, Bo</creator><creator>Li, Wei</creator><creator>Sun, Yulin</creator><creator>Zhou, Lanping</creator><creator>Xu, Yang</creator><creator>Zhao, Xiaohang</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>AEUYN</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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140918</creationdate><title>A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1</title><author>Han, Bo ; Li, Wei ; Sun, Yulin ; Zhou, Lanping ; Xu, Yang ; Zhao, Xiaohang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c622t-771ea403a0bbb59bc8adea0e7cafd320bdf1397b00721408c9cc71a263e98b7b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Analysis</topic><topic>Antioxidants</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Arsenic</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Biology and Life Sciences</topic><topic>BNIP3 protein</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer genetics</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Caspase</topic><topic>Cell cycle</topic><topic>Cell Cycle Proteins - biosynthesis</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell death</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cytometry</topic><topic>Cytotoxicity</topic><topic>Esophageal cancer</topic><topic>Esophageal Neoplasms - drug therapy</topic><topic>Esophageal Squamous Cell Carcinoma</topic><topic>Esophagus</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Humans</topic><topic>Hydroxybenzoates - 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drug effects</topic><topic>Seeds</topic><topic>Signaling</topic><topic>siRNA</topic><topic>Squamous cell carcinoma</topic><topic>Studies</topic><topic>Up-regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Bo</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Sun, Yulin</creatorcontrib><creatorcontrib>Zhou, Lanping</creatorcontrib><creatorcontrib>Xu, Yang</creatorcontrib><creatorcontrib>Zhao, Xiaohang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Bo</au><au>Li, Wei</au><au>Sun, Yulin</au><au>Zhou, Lanping</au><au>Xu, Yang</au><au>Zhao, Xiaohang</au><au>Sarkar, Devanand</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-09-18</date><risdate>2014</risdate><volume>9</volume><issue>9</issue><spage>e107204</spage><epage>e107204</epage><pages>e107204-e107204</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate is an antioxidant found in the testa of peanut seeds. Previous studies have shown that ethyl-3,4-dihydroxybenzoate can effectively reduce breast cancer cell metastasis by inhibiting prolyl-hydroxylase. In this study, we investigated the cytotoxic effect of ethyl-3,4-dihydroxybenzoate on esophageal squamous cell carcinoma cells in vitro and identified key regulators of ethyl-3,4-dihydroxybenzoate-induced esophageal cancer cell death through transcription expression profiling. Using flow cytometry analysis, we found that ethyl-3,4-dihydroxybenzoate induced S phase accumulation, a loss in mitochondrial membrane permeabilization, and caspase-dependent apoptosis. Moreover, an expression profile analysis identified 46 up- and 9 down-regulated genes in esophageal cancer KYSE 170 cells treated with ethyl-3,4-dihydroxybenzoate. These differentially expressed genes are involved in several signaling pathways associated with cell cycle regulation and cellular metabolism. Consistent with the expression profile results, the transcriptional and protein expression levels of candidate genes NDRG1, BNIP3, AKR1C1, CCNG2 and VEGFA were found to be significantly increased in treated KYSE 170 cells by reverse-transcription PCR and western blot analysis. We also found that protein levels of hypoxia-inducible factor-1α, BNIP3, Beclin and NDRG1 were increased and that enriched expression of BNIP3 and Beclin caused autophagy mediated by microtubule-associated protein 1 light chain 3 in the treated cells. Autophagy and apoptosis were activated together in esophageal cancer cells after exposed to ethyl-3,4-dihydroxybenzoate. Furthermore, knock-down of NDRG1 expression by siRNA significantly attenuated apoptosis in the cancer cells, implying that NDRG1 may be required for ethyl-3,4-dihydroxybenzoate-induced apoptosis. Together, these results suggest that the cytotoxic effects of ethyl-3,4-dihydroxybenzoate were mediated by the up-regulation of NDRG1, BNIP3, Beclin and hypoxia-inducible factor-1α, initiating BNIP3 and Beclin mediated autophagy at an early stage and ultimately resulting in esophageal cancer cell apoptosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25232961</pmid><doi>10.1371/journal.pone.0107204</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-09, Vol.9 (9), p.e107204-e107204 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1563048790 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analysis Antioxidants Apoptosis Apoptosis - drug effects Apoptosis - genetics Arsenic Autophagy Autophagy - drug effects Biology and Life Sciences BNIP3 protein Breast cancer Cancer Cancer genetics Carcinoma, Squamous Cell - drug therapy Caspase Cell cycle Cell Cycle Proteins - biosynthesis Cell Cycle Proteins - genetics Cell death Cell growth Cell Line, Tumor Cell Membrane Permeability - drug effects Cell Proliferation - drug effects Cell Survival - drug effects Cytometry Cytotoxicity Esophageal cancer Esophageal Neoplasms - drug therapy Esophageal Squamous Cell Carcinoma Esophagus Flow cytometry Gene expression Genes Humans Hydroxybenzoates - pharmacology Hydroxylase Hypoxia Hypoxia-inducible factors Immunoglobulins Intracellular Signaling Peptides and Proteins - biosynthesis Intracellular Signaling Peptides and Proteins - genetics Laboratories Life sciences Medicine and Health Sciences Membrane Proteins - biosynthesis Metabolism Metastases Microtubule-associated protein 1 Mitochondria Mitochondrial Membranes - physiology Myc protein Oncology Phagocytosis Polyphenols Prolyl-Hydroxylase Inhibitors - pharmacology Proteins Proto-Oncogene Proteins - biosynthesis Protocatechuic acid Regulators Resveratrol RNA Interference RNA, Small Interfering S phase S Phase Cell Cycle Checkpoints - drug effects Seeds Signaling siRNA Squamous cell carcinoma Studies Up-regulation |
| title | A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells via up-regulation of BNIP3 and N-myc downstream-regulated gene-1 |
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