Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells
PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines. We examined the effects of treatment with t...
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| Veröffentlicht in: | Anticancer research 2013-03, Vol.33 (3), p.809-813 |
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| container_title | Anticancer research |
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| creator | Ono, Aya Oike, Ryo Okuhashi, Yuki Takahashi, Yusuke Itoh, Mai Nara, Nobuo Tohda, Shuji |
| description | PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines.
We examined the effects of treatment with these inhibitors on cell growth and protein expression.
PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another.
PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways. |
| format | Article |
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We examined the effects of treatment with these inhibitors on cell growth and protein expression.
PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another.
PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways.</description><identifier>ISSN: 0250-7005</identifier><identifier>EISSN: 1791-7530</identifier><identifier>PMID: 23482748</identifier><language>eng</language><publisher>Greece</publisher><subject>Cell Line, Tumor ; Cell Proliferation - drug effects ; Gene Expression - drug effects ; Humans ; Indoles - pharmacology ; Leukemia - drug therapy ; Leukemia - pathology ; Phosphorylation ; Purines - pharmacology ; Receptors, Notch - physiology ; Ribosomal Protein S6 Kinases - metabolism ; Signal Transduction - drug effects ; Sirolimus - pharmacology ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; TOR Serine-Threonine Kinases - physiology</subject><ispartof>Anticancer research, 2013-03, Vol.33 (3), p.809-813</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23482748$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ono, Aya</creatorcontrib><creatorcontrib>Oike, Ryo</creatorcontrib><creatorcontrib>Okuhashi, Yuki</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Itoh, Mai</creatorcontrib><creatorcontrib>Nara, Nobuo</creatorcontrib><creatorcontrib>Tohda, Shuji</creatorcontrib><title>Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells</title><title>Anticancer research</title><addtitle>Anticancer Res</addtitle><description>PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines.
We examined the effects of treatment with these inhibitors on cell growth and protein expression.
PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another.
PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways.</description><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Gene Expression - drug effects</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Leukemia - drug therapy</subject><subject>Leukemia - pathology</subject><subject>Phosphorylation</subject><subject>Purines - pharmacology</subject><subject>Receptors, Notch - physiology</subject><subject>Ribosomal Protein S6 Kinases - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - pharmacology</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>TOR Serine-Threonine Kinases - physiology</subject><issn>0250-7005</issn><issn>1791-7530</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1Lw0AQBuBFFBurf0H26CWw38kepfhRKLZIPYdpMltWs0nMJkL_vVErePM0MDzvMDMnJOGZ5WmmJTslCROapRljekYuYnxlzBiby3MyE1LlIlN5QqpFGzroYfAfSNE5LIdIW0c3G6EEhaaiPXQQDqVvaNvQsF0_0-j3DdS1b_bf4Gm9XTz-bU60xvENgwdaYl3HS3LmoI54daxz8nJ_N4XS1fphubhdpZ1QakiV0NI60K7URhhrUDCXSy3A6cpY6SRKYQVXpTWwYzaTklU75ixy5KBNKefk5mdu17fvI8ahCD5-bQANtmMsuDTT0YpP0f8pzxSzOdMTvT7ScRewKrreB-gPxe8T5SetL2y2</recordid><startdate>201303</startdate><enddate>201303</enddate><creator>Ono, Aya</creator><creator>Oike, Ryo</creator><creator>Okuhashi, Yuki</creator><creator>Takahashi, Yusuke</creator><creator>Itoh, Mai</creator><creator>Nara, Nobuo</creator><creator>Tohda, Shuji</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>201303</creationdate><title>Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells</title><author>Ono, Aya ; Oike, Ryo ; Okuhashi, Yuki ; Takahashi, Yusuke ; Itoh, Mai ; Nara, Nobuo ; Tohda, Shuji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p244t-42539fa5fc562696e20f8352af5d693f3e329214c96ab097330db0f9e1e1a56c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Gene Expression - drug effects</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Leukemia - drug therapy</topic><topic>Leukemia - pathology</topic><topic>Phosphorylation</topic><topic>Purines - pharmacology</topic><topic>Receptors, Notch - physiology</topic><topic>Ribosomal Protein S6 Kinases - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - pharmacology</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>TOR Serine-Threonine Kinases - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ono, Aya</creatorcontrib><creatorcontrib>Oike, Ryo</creatorcontrib><creatorcontrib>Okuhashi, Yuki</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Itoh, Mai</creatorcontrib><creatorcontrib>Nara, Nobuo</creatorcontrib><creatorcontrib>Tohda, Shuji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Anticancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ono, Aya</au><au>Oike, Ryo</au><au>Okuhashi, Yuki</au><au>Takahashi, Yusuke</au><au>Itoh, Mai</au><au>Nara, Nobuo</au><au>Tohda, Shuji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells</atitle><jtitle>Anticancer research</jtitle><addtitle>Anticancer Res</addtitle><date>2013-03</date><risdate>2013</risdate><volume>33</volume><issue>3</issue><spage>809</spage><epage>813</epage><pages>809-813</pages><issn>0250-7005</issn><eissn>1791-7530</eissn><abstract>PP242 is a compound which inhibits both mammalian target of rapamycin complex-1 (mTORC1) and mTORC2. We examined the effects of PP242 and rapamycin on mTOR signalling and evaluated potential crosstalk with the NOTCH signalling in eight leukemia cell lines.
We examined the effects of treatment with these inhibitors on cell growth and protein expression.
PP242 suppressed growth more potently than did rapamycin. In two cell lines poorly sensitive to PP242, PP242 failed to inhibit v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation. Suppression of mTOR phosphorylation was weaker in myeloid cell lines. Rapamycin induced eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation in three cell lines. Phosphorylation of both isoforms (p70 and p85) of S6 kinase (S6K) was suppressed in three cell lines; only p70 was suppressed in the others. NOTCH1 expression and activation were up-regulated by PP242 in one cell line but down-regulated in another.
PP242 is a candidate for molecular-targeted leukemia therapy, although its effects must be evaluated on a case-by-case basis. Crosstalk was found between the mTOR and NOTCH signalling pathways.</abstract><cop>Greece</cop><pmid>23482748</pmid><tpages>5</tpages></addata></record> |
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| ispartof | Anticancer research, 2013-03, Vol.33 (3), p.809-813 |
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| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Cell Line, Tumor Cell Proliferation - drug effects Gene Expression - drug effects Humans Indoles - pharmacology Leukemia - drug therapy Leukemia - pathology Phosphorylation Purines - pharmacology Receptors, Notch - physiology Ribosomal Protein S6 Kinases - metabolism Signal Transduction - drug effects Sirolimus - pharmacology TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - physiology |
| title | Comparative effects of PP242 and rapamycin on mTOR signalling and NOTCH signalling in leukemia cells |
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