A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase
ABSTRACT 1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of R...
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| Veröffentlicht in: | Journal of cellular biochemistry 2015-08, Vol.116 (8), p.1595-1601 |
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| creator | Kost, Gina Chun Yang, Mi Young Li, Liangwei Zhang, Yinwei Liu, Chia-yi Kim, Deog Joong Ahn, Chang-Ho Lee, Young Bok Liu, Zhi-Ren |
| description | ABSTRACT
1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX‐5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of 3H‐labeled RX‐5902 to Y593 phospho‐p68 RNA helicase. We further demonstrated RX‐5902 inhibited the β‐catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX‐5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β‐catenin pathway, such as c‐Myc, cyclin D1 and p‐c‐Jun. Therefore, our study indicates that the inhibition of Y593 phospho‐p68 helicase ‐ β‐catenin interaction by direct binding of RX‐5902 to Y593 phospho‐p68 RNA helicase may contribute to the anti‐cancer activity of this compound. J. Cell. Biochem. 116: 1595–1601, 2015. © 2015 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/jcb.25113 |
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1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX‐5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of 3H‐labeled RX‐5902 to Y593 phospho‐p68 RNA helicase. We further demonstrated RX‐5902 inhibited the β‐catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX‐5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β‐catenin pathway, such as c‐Myc, cyclin D1 and p‐c‐Jun. Therefore, our study indicates that the inhibition of Y593 phospho‐p68 helicase ‐ β‐catenin interaction by direct binding of RX‐5902 to Y593 phospho‐p68 RNA helicase may contribute to the anti‐cancer activity of this compound. J. Cell. Biochem. 116: 1595–1601, 2015. © 2015 Wiley Periodicals, Inc.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.25113</identifier><identifier>PMID: 25649741</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>ANTI-CANCER ; Antineoplastic Agents - pharmacology ; beta Catenin - metabolism ; Binding ; Binding Sites - drug effects ; Cancer ; Catenin ; Cell Line, Tumor ; Cyclin D1 ; DEAD-box RNA Helicases - chemistry ; DEAD-box RNA Helicases - metabolism ; DNA helicase ; Gene expression ; Humans ; Myc protein ; Neoplasms - drug therapy ; Neoplasms - metabolism ; p68 RNA HELICASE ; PHOSPHO-p68 ; Phosphorylation ; Piperazine ; Piperazines - pharmacology ; Protein Binding - drug effects ; Quinoxalines - pharmacology ; Ribonucleic acid ; RNA ; RNA helicase ; RX-5902 ; Signal Transduction - drug effects ; Tumor cell lines</subject><ispartof>Journal of cellular biochemistry, 2015-08, Vol.116 (8), p.1595-1601</ispartof><rights>2015 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3393-e1bbbef0e1cfc8f59fa0f5966cafd3e949c214f18a44d3bc3b169ea1a310e17f3</citedby><cites>FETCH-LOGICAL-c3393-e1bbbef0e1cfc8f59fa0f5966cafd3e949c214f18a44d3bc3b169ea1a310e17f3</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%2Fjcb.25113$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.25113$$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/25649741$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kost, Gina Chun</creatorcontrib><creatorcontrib>Yang, Mi Young</creatorcontrib><creatorcontrib>Li, Liangwei</creatorcontrib><creatorcontrib>Zhang, Yinwei</creatorcontrib><creatorcontrib>Liu, Chia-yi</creatorcontrib><creatorcontrib>Kim, Deog Joong</creatorcontrib><creatorcontrib>Ahn, Chang-Ho</creatorcontrib><creatorcontrib>Lee, Young Bok</creatorcontrib><creatorcontrib>Liu, Zhi-Ren</creatorcontrib><title>A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase</title><title>Journal of cellular biochemistry</title><addtitle>J. Cell. Biochem</addtitle><description>ABSTRACT
1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX‐5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of 3H‐labeled RX‐5902 to Y593 phospho‐p68 RNA helicase. We further demonstrated RX‐5902 inhibited the β‐catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX‐5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β‐catenin pathway, such as c‐Myc, cyclin D1 and p‐c‐Jun. Therefore, our study indicates that the inhibition of Y593 phospho‐p68 helicase ‐ β‐catenin interaction by direct binding of RX‐5902 to Y593 phospho‐p68 RNA helicase may contribute to the anti‐cancer activity of this compound. J. Cell. Biochem. 116: 1595–1601, 2015. © 2015 Wiley Periodicals, Inc.</description><subject>ANTI-CANCER</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>beta Catenin - metabolism</subject><subject>Binding</subject><subject>Binding Sites - drug effects</subject><subject>Cancer</subject><subject>Catenin</subject><subject>Cell Line, Tumor</subject><subject>Cyclin D1</subject><subject>DEAD-box RNA Helicases - chemistry</subject><subject>DEAD-box RNA Helicases - metabolism</subject><subject>DNA helicase</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Myc protein</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>p68 RNA HELICASE</subject><subject>PHOSPHO-p68</subject><subject>Phosphorylation</subject><subject>Piperazine</subject><subject>Piperazines - pharmacology</subject><subject>Protein Binding - drug effects</subject><subject>Quinoxalines - pharmacology</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA helicase</subject><subject>RX-5902</subject><subject>Signal Transduction - drug effects</subject><subject>Tumor cell lines</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFktFu0zAYhSMEYmNwwQsgS9y0Ur3ZceLUl6XQbagrZRpaASHLcf8sLqmdOQm0PBYvwR3PhKHbLpAQN7Ysf-fo_3VOFD2l5JASEh-tdH4Yp5Sye9E-JSLDCU-S-9E-yRjBMaPxXvSoaVaEECFY_DDai1OeiCyh-9GPEZq5L1ChkW0NHiurwaPRFdh2gCjusUGKX5o1tKXbbOsS7Lbq4wR_7HE8qTrnHY7x2e73ujPWbVRlLGY4YKN1eGvlcxdEn9Dc1ODVN2MB9c4XOBUk7g_QqW3BF-ChQZemLdHP72GGFqyxaNJZ3Rpn0UXpXXdVovepYGheuqYuHa75EJ3PRugEKqNVA4-jB4WqGnhycx9E7yavLsYnePrm-HQ8mmLNmGAYaJ7nUBCgutDDIhWFIuHkXKtiyUAkQsc0KehQJcmS5ZrllAtQVDEaNFnBDqLezrf27rqDppVr02ioKmXBdY2kGRF0yAiP_49yQXhKOUsC-vwvdOU6b8MikoU8mUgYJ4Hq7yjtXdN4KGTtzVr5raRE_i6CDEWQf4oQ2Gc3jl2-huUdeZt8AI52wFdTwfbfTvL1-MWtJd4pTNPC5k6h_GfJM5al8nJ2LKfp_G36YXEmF-wXHIjKWw</recordid><startdate>201508</startdate><enddate>201508</enddate><creator>Kost, Gina Chun</creator><creator>Yang, Mi Young</creator><creator>Li, Liangwei</creator><creator>Zhang, Yinwei</creator><creator>Liu, Chia-yi</creator><creator>Kim, Deog Joong</creator><creator>Ahn, Chang-Ho</creator><creator>Lee, Young Bok</creator><creator>Liu, Zhi-Ren</creator><general>Blackwell Publishing Ltd</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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T7</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>7TM</scope></search><sort><creationdate>201508</creationdate><title>A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase</title><author>Kost, Gina Chun ; Yang, Mi Young ; Li, Liangwei ; Zhang, Yinwei ; Liu, Chia-yi ; Kim, Deog Joong ; Ahn, Chang-Ho ; Lee, Young Bok ; Liu, Zhi-Ren</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3393-e1bbbef0e1cfc8f59fa0f5966cafd3e949c214f18a44d3bc3b169ea1a310e17f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>ANTI-CANCER</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>beta Catenin - metabolism</topic><topic>Binding</topic><topic>Binding Sites - drug effects</topic><topic>Cancer</topic><topic>Catenin</topic><topic>Cell Line, Tumor</topic><topic>Cyclin D1</topic><topic>DEAD-box RNA Helicases - chemistry</topic><topic>DEAD-box RNA Helicases - metabolism</topic><topic>DNA helicase</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Myc protein</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>p68 RNA HELICASE</topic><topic>PHOSPHO-p68</topic><topic>Phosphorylation</topic><topic>Piperazine</topic><topic>Piperazines - pharmacology</topic><topic>Protein Binding - drug effects</topic><topic>Quinoxalines - pharmacology</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA helicase</topic><topic>RX-5902</topic><topic>Signal Transduction - drug effects</topic><topic>Tumor cell lines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kost, Gina Chun</creatorcontrib><creatorcontrib>Yang, Mi Young</creatorcontrib><creatorcontrib>Li, Liangwei</creatorcontrib><creatorcontrib>Zhang, Yinwei</creatorcontrib><creatorcontrib>Liu, Chia-yi</creatorcontrib><creatorcontrib>Kim, Deog Joong</creatorcontrib><creatorcontrib>Ahn, Chang-Ho</creatorcontrib><creatorcontrib>Lee, Young Bok</creatorcontrib><creatorcontrib>Liu, Zhi-Ren</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>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Journal of cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kost, Gina Chun</au><au>Yang, Mi Young</au><au>Li, Liangwei</au><au>Zhang, Yinwei</au><au>Liu, Chia-yi</au><au>Kim, Deog Joong</au><au>Ahn, Chang-Ho</au><au>Lee, Young Bok</au><au>Liu, Zhi-Ren</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase</atitle><jtitle>Journal of cellular biochemistry</jtitle><addtitle>J. Cell. Biochem</addtitle><date>2015-08</date><risdate>2015</risdate><volume>116</volume><issue>8</issue><spage>1595</spage><epage>1601</epage><pages>1595-1601</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><abstract>ABSTRACT
1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX‐5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of 3H‐labeled RX‐5902 to Y593 phospho‐p68 RNA helicase. We further demonstrated RX‐5902 inhibited the β‐catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX‐5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β‐catenin pathway, such as c‐Myc, cyclin D1 and p‐c‐Jun. Therefore, our study indicates that the inhibition of Y593 phospho‐p68 helicase ‐ β‐catenin interaction by direct binding of RX‐5902 to Y593 phospho‐p68 RNA helicase may contribute to the anti‐cancer activity of this compound. J. Cell. Biochem. 116: 1595–1601, 2015. © 2015 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>25649741</pmid><doi>10.1002/jcb.25113</doi><tpages>7</tpages></addata></record> |
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| subjects | ANTI-CANCER Antineoplastic Agents - pharmacology beta Catenin - metabolism Binding Binding Sites - drug effects Cancer Catenin Cell Line, Tumor Cyclin D1 DEAD-box RNA Helicases - chemistry DEAD-box RNA Helicases - metabolism DNA helicase Gene expression Humans Myc protein Neoplasms - drug therapy Neoplasms - metabolism p68 RNA HELICASE PHOSPHO-p68 Phosphorylation Piperazine Piperazines - pharmacology Protein Binding - drug effects Quinoxalines - pharmacology Ribonucleic acid RNA RNA helicase RX-5902 Signal Transduction - drug effects Tumor cell lines |
| title | A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase |
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