MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells
Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, an...
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| Veröffentlicht in: | International journal of oncology 2014-03, Vol.44 (3), p.905-911 |
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| creator | LEE, SUN HWA KANG, YONG JUNG SUNG, BOKYUNG KIM, DONG HWAN LIM, HYUN SOOK KIM, HYE RIM KIM, SEONG JIN YOON, JEONG-HYUN MOON, HYUNG RYONG CHUNG, HAE YOUNG KIM, NAM DEUK |
| description | Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild-type (p53-wt) LNCaP (androgen-dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells. |
| doi_str_mv | 10.3892/ijo.2014.2257 |
| format | Article |
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In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild-type (p53-wt) LNCaP (androgen-dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.2014.2257</identifier><identifier>PMID: 24424889</identifier><language>eng</language><publisher>Greece: D.A. Spandidos</publisher><subject>Akt ; Androgens ; Antimitotic agents ; Antineoplastic agents ; Apoptosis ; Apoptosis - drug effects ; Benzofurans - pharmacology ; Breast cancer ; Cancer ; Cancer therapies ; Cell cycle ; Cell death ; Cell growth ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Colorectal cancer ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; Dosage and administration ; Drug therapy ; extracellular signal-regulated kinase ; Extracellular signal-regulated kinases ; Forkhead Box Protein O1 ; Forkhead Transcription Factors - biosynthesis ; Forkhead Transcription Factors - genetics ; FoxO1 ; Gene Expression Regulation, Neoplastic - drug effects ; HCT116 Cells ; Health aspects ; Humans ; Kinases ; Ligands ; Male ; MAP Kinase Signaling System - drug effects ; MHY-449 ; Molecular biology ; Naphthyridines - pharmacology ; Oncology, Experimental ; Phosphorylation ; Phosphorylation - drug effects ; Prostate cancer ; prostate cancer cells ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Proteins ; Proto-Oncogene Proteins c-akt - biosynthesis ; Proto-Oncogene Proteins c-akt - genetics</subject><ispartof>International journal of oncology, 2014-03, Vol.44 (3), p.905-911</ispartof><rights>Copyright © 2014, Spandidos Publications</rights><rights>COPYRIGHT 2014 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-b036fe1d7519272e0629f3f094b8052798e92d713c63581effca7659eed9f2c83</citedby><cites>FETCH-LOGICAL-c490t-b036fe1d7519272e0629f3f094b8052798e92d713c63581effca7659eed9f2c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,5571,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24424889$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LEE, SUN HWA</creatorcontrib><creatorcontrib>KANG, YONG JUNG</creatorcontrib><creatorcontrib>SUNG, BOKYUNG</creatorcontrib><creatorcontrib>KIM, DONG HWAN</creatorcontrib><creatorcontrib>LIM, HYUN SOOK</creatorcontrib><creatorcontrib>KIM, HYE RIM</creatorcontrib><creatorcontrib>KIM, SEONG JIN</creatorcontrib><creatorcontrib>YOON, JEONG-HYUN</creatorcontrib><creatorcontrib>MOON, HYUNG RYONG</creatorcontrib><creatorcontrib>CHUNG, HAE YOUNG</creatorcontrib><creatorcontrib>KIM, NAM DEUK</creatorcontrib><title>MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild-type (p53-wt) LNCaP (androgen-dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.</description><subject>Akt</subject><subject>Androgens</subject><subject>Antimitotic agents</subject><subject>Antineoplastic agents</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Benzofurans - pharmacology</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Colorectal cancer</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>extracellular signal-regulated kinase</subject><subject>Extracellular signal-regulated kinases</subject><subject>Forkhead Box Protein O1</subject><subject>Forkhead Transcription Factors - biosynthesis</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>FoxO1</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>HCT116 Cells</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MHY-449</subject><subject>Molecular biology</subject><subject>Naphthyridines - pharmacology</subject><subject>Oncology, Experimental</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Prostate cancer</subject><subject>prostate cancer cells</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - biosynthesis</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNptkl1rFDEUhgdRbK1eeisBQW8223zNRy6XpbVipSJ6IaUM2XzsZJ1JpkmmuP44f5tZty4WJBcnhOe8nPPmLYqXGM1pw8mp3fg5QZjNCSnrR8UxrjmGhBH6ON8R5rBilB8Vz2LcIETKEuGnxRFhjLCm4cfFr48X3yBjfAYEcP5O90DZbquCX2n305sp-Gs2K-Hq5hrPmhvgxNilbhussg5W0DsNlA72TiR7p2fAOjVJHYEY_Zh8shJI3WdJLVIHUhf8tO7A4NXU5wbvgDdg8T2dnvsfVxgIp8DZ5w8g2rUTvXXrLAc-LSnopkE4MAYfk0gaSOGkDn-U4_PiiRF91C_u60nx9fzsy_ICXl69e79cXELJOEpwhWhlNFZ1iTmpiUYV4YYaxNmqQSWpeaM5UTWmsqJlg7UxUtRVybVW3BDZ0JPi9V43T3E76ZjajZ9CHjO2mFNCKapyPVBr0evWOuNTEHKwUbYLhrP5VdmwTM3_Q-Wj9GBlttTY_P6g4c0_DZ0Wfeqi76edhfEhCPegzF7FoE07BjuIsG0xandpaXNa2l1a2l1aMv_qfqtpNWh1oP_GIwNv90Ac8-9Y5eOByUo5NxBRiDgq6W-X9sWT</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>LEE, SUN HWA</creator><creator>KANG, YONG JUNG</creator><creator>SUNG, BOKYUNG</creator><creator>KIM, DONG HWAN</creator><creator>LIM, HYUN SOOK</creator><creator>KIM, HYE RIM</creator><creator>KIM, SEONG JIN</creator><creator>YOON, JEONG-HYUN</creator><creator>MOON, HYUNG RYONG</creator><creator>CHUNG, HAE YOUNG</creator><creator>KIM, NAM DEUK</creator><general>D.A. Spandidos</general><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20140301</creationdate><title>MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells</title><author>LEE, SUN HWA ; KANG, YONG JUNG ; SUNG, BOKYUNG ; KIM, DONG HWAN ; LIM, HYUN SOOK ; KIM, HYE RIM ; KIM, SEONG JIN ; YOON, JEONG-HYUN ; MOON, HYUNG RYONG ; CHUNG, HAE YOUNG ; KIM, NAM DEUK</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-b036fe1d7519272e0629f3f094b8052798e92d713c63581effca7659eed9f2c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Akt</topic><topic>Androgens</topic><topic>Antimitotic agents</topic><topic>Antineoplastic agents</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Benzofurans - pharmacology</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell death</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Colorectal cancer</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>extracellular signal-regulated kinase</topic><topic>Extracellular signal-regulated kinases</topic><topic>Forkhead Box Protein O1</topic><topic>Forkhead Transcription Factors - biosynthesis</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>FoxO1</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>HCT116 Cells</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Male</topic><topic>MAP Kinase Signaling System - 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In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild-type (p53-wt) LNCaP (androgen-dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.</abstract><cop>Greece</cop><pub>D.A. Spandidos</pub><pmid>24424889</pmid><doi>10.3892/ijo.2014.2257</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1019-6439 |
| ispartof | International journal of oncology, 2014-03, Vol.44 (3), p.905-911 |
| issn | 1019-6439 1791-2423 |
| language | eng |
| recordid | cdi_proquest_journals_1932330619 |
| source | Spandidos Publications Journals; MEDLINE; Alma/SFX Local Collection; EZB Electronic Journals Library |
| subjects | Akt Androgens Antimitotic agents Antineoplastic agents Apoptosis Apoptosis - drug effects Benzofurans - pharmacology Breast cancer Cancer Cancer therapies Cell cycle Cell death Cell growth Cell Line, Tumor Cell Proliferation - drug effects Colorectal cancer Cytotoxicity Deoxyribonucleic acid DNA Dosage and administration Drug therapy extracellular signal-regulated kinase Extracellular signal-regulated kinases Forkhead Box Protein O1 Forkhead Transcription Factors - biosynthesis Forkhead Transcription Factors - genetics FoxO1 Gene Expression Regulation, Neoplastic - drug effects HCT116 Cells Health aspects Humans Kinases Ligands Male MAP Kinase Signaling System - drug effects MHY-449 Molecular biology Naphthyridines - pharmacology Oncology, Experimental Phosphorylation Phosphorylation - drug effects Prostate cancer prostate cancer cells Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Proteins Proto-Oncogene Proteins c-akt - biosynthesis Proto-Oncogene Proteins c-akt - genetics |
| title | MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T06%3A41%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MHY-449,%20a%20novel%20dihydrobenzofuro%5B4,5-b%5D%5B1,8%5D%20naphthyridin-6-one%20derivative,%20induces%20apoptotic%20cell%20death%20through%20modulation%20of%20Akt/FoxO1%20and%20ERK%20signaling%20in%20PC3%20human%20prostate%20cancer%20cells&rft.jtitle=International%20journal%20of%20oncology&rft.au=LEE,%20SUN%20HWA&rft.date=2014-03-01&rft.volume=44&rft.issue=3&rft.spage=905&rft.epage=911&rft.pages=905-911&rft.issn=1019-6439&rft.eissn=1791-2423&rft_id=info:doi/10.3892/ijo.2014.2257&rft_dat=%3Cgale_proqu%3EA412556584%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1932330619&rft_id=info:pmid/24424889&rft_galeid=A412556584&rfr_iscdi=true |