Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling
Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signal...
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| Veröffentlicht in: | Oncogene 2010-01, Vol.29 (1), p.139-149 |
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| creator | Yalcin, A Clem, B Makoni, S Clem, A Nelson, K Thornburg, J Siow, D Lane, A N Brock, S E Goswami, U Eaton, J W Telang, S Chesney, J |
| description | Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras
V12
in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways. |
| doi_str_mv | 10.1038/onc.2009.317 |
| format | Article |
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V12
in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2009.317</identifier><identifier>PMID: 19855431</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Apoptosis ; Biochemistry ; Biological and medical sciences ; Blotting, Western ; Cancer ; Care and treatment ; Cell Biology ; Cell Line, Transformed ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular signal transduction ; Choline Kinase - genetics ; Choline Kinase - metabolism ; Enzyme inhibitors ; Female ; Fundamental and applied biological sciences. Psychology ; Genetic aspects ; Genetics ; Health aspects ; HeLa Cells ; Human Genetics ; Humans ; Internal Medicine ; Lipids ; Magnetic Resonance Spectroscopy ; Medicine ; Medicine & Public Health ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases - metabolism ; Molecular and cellular biology ; Neoplasms, Experimental - genetics ; Neoplasms, Experimental - metabolism ; Neoplasms, Experimental - pathology ; Oncology ; original-article ; Phosphatidic Acids - metabolism ; Phosphatidylcholines - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylcholine - metabolism ; Physiological aspects ; Protein kinases ; Proto-Oncogene Proteins c-akt - metabolism ; ras Proteins - genetics ; ras Proteins - metabolism ; RNA Interference ; Signal Transduction ; Survival Analysis ; Transplantation, Heterologous ; Tumor Burden</subject><ispartof>Oncogene, 2010-01, Vol.29 (1), p.139-149</ispartof><rights>Macmillan Publishers Limited 2010</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 7, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-ad4d0e38146bc3a325f1c274c89735bc4b6fcf969cdb3d448cfdaf56f7ab95dc3</citedby><cites>FETCH-LOGICAL-c587t-ad4d0e38146bc3a325f1c274c89735bc4b6fcf969cdb3d448cfdaf56f7ab95dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2009.317$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2009.317$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22323257$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19855431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yalcin, A</creatorcontrib><creatorcontrib>Clem, B</creatorcontrib><creatorcontrib>Makoni, S</creatorcontrib><creatorcontrib>Clem, A</creatorcontrib><creatorcontrib>Nelson, K</creatorcontrib><creatorcontrib>Thornburg, J</creatorcontrib><creatorcontrib>Siow, D</creatorcontrib><creatorcontrib>Lane, A N</creatorcontrib><creatorcontrib>Brock, S E</creatorcontrib><creatorcontrib>Goswami, U</creatorcontrib><creatorcontrib>Eaton, J W</creatorcontrib><creatorcontrib>Telang, S</creatorcontrib><creatorcontrib>Chesney, J</creatorcontrib><title>Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras
V12
in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell Line, Transformed</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cellular signal transduction</subject><subject>Choline Kinase - genetics</subject><subject>Choline Kinase - metabolism</subject><subject>Enzyme inhibitors</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Health aspects</subject><subject>HeLa Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Lipids</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Molecular and cellular biology</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphatidic Acids - metabolism</subject><subject>Phosphatidylcholines - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylcholine - metabolism</subject><subject>Physiological aspects</subject><subject>Protein kinases</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>ras Proteins - genetics</subject><subject>ras Proteins - metabolism</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Survival Analysis</subject><subject>Transplantation, Heterologous</subject><subject>Tumor Burden</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp90t1r1TAYB-AgijtO77yWoqg39izfaS4PQ904EwfOOyGk-TjLbJPZtML-e1N62NgYkotC-rxv3vRXAF4juEaQNEcpmjWGUK4JEk_AClHBa8YkfQpWUDJYS0zwAXiR8xWEUEiIn4MDJBvGKEEr8OuH65wZw19XhXgZ2jCGFKvkK3OZuhBd9TtEnV2VQz91o44uTbm7qfQ4ujjp0eXq2-Z8W-loq_NTsj3abC-K3UVdincvwTOvu-xe7Z-H4OeXzxfHJ_XZ96-nx5uz2rBGjLW21EJHGkR5a4gmmHlksKCmkYKw1tCWe-Mll8a2xFLaGG-1Z9wL3UpmDTkEH5e-10P6M7k8qj5k47pumVcJQjHGUvAiP_xXYkRg00hY4NsH8CpNQ7lWMbj0g4jLgt4taKc7p0L0aRy0mTuqDUacE4TorNaPqLKs64NJ0flQ9u8VfFoKzJByHpxX10Po9XCjEFRz5qpkrubMVcm88Df7Uae2d_YO70Mu4P0e6Gx05wcdTci3DpcfpHzzuVG9uFxexZ0b7u786MH_ANVEwU0</recordid><startdate>20100107</startdate><enddate>20100107</enddate><creator>Yalcin, A</creator><creator>Clem, B</creator><creator>Makoni, S</creator><creator>Clem, A</creator><creator>Nelson, K</creator><creator>Thornburg, J</creator><creator>Siow, D</creator><creator>Lane, A N</creator><creator>Brock, S E</creator><creator>Goswami, U</creator><creator>Eaton, J W</creator><creator>Telang, S</creator><creator>Chesney, J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20100107</creationdate><title>Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling</title><author>Yalcin, A ; Clem, B ; Makoni, S ; Clem, A ; Nelson, K ; Thornburg, J ; Siow, D ; Lane, A N ; Brock, S E ; Goswami, U ; Eaton, J W ; Telang, S ; Chesney, J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-ad4d0e38146bc3a325f1c274c89735bc4b6fcf969cdb3d448cfdaf56f7ab95dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell Line, Transformed</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cellular signal transduction</topic><topic>Choline Kinase - genetics</topic><topic>Choline Kinase - metabolism</topic><topic>Enzyme inhibitors</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yalcin, A</au><au>Clem, B</au><au>Makoni, S</au><au>Clem, A</au><au>Nelson, K</au><au>Thornburg, J</au><au>Siow, D</au><au>Lane, A N</au><au>Brock, S E</au><au>Goswami, U</au><au>Eaton, J W</au><au>Telang, S</au><au>Chesney, J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2010-01-07</date><risdate>2010</risdate><volume>29</volume><issue>1</issue><spage>139</spage><epage>149</epage><pages>139-149</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Choline is an essential anabolic substrate for the synthesis of phospholipids. Choline kinase phosphorylates choline to phosphocholine that serves as a precursor for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the synthesis of lipid signaling molecules. Nuclear magnetic resonance (NMR)-based metabolomic studies of human tumors have identified a marked increase in the intracellular concentration of phosphocholine relative to normal tissues. We postulated that the observed intracellular pooling of phosphocholine may be required to sustain the production of the pleiotropic lipid second messenger, phosphatidic acid. Phosphatidic acid is generated from the cleavage of phosphatidylcholine by phospholipase D2 and is a key activator of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT survival signaling pathways. In this study we show that the steady-state concentration of phosphocholine is increased by the ectopic expression of oncogenic H-Ras
V12
in immortalized human bronchial epithelial cells. We then find that small interfering RNA (siRNA) silencing of choline kinase expression in transformed HeLa cells completely abrogates the high concentration of phosphocholine, which in turn decreases phosphatidylcholine, phosphatidic acid and signaling through the MAPK and PI3K/AKT pathways. This simultaneous reduction in survival signaling markedly decreases the anchorage-independent survival of HeLa cells in soft agar and in athymic mice. Last, we confirm the relative importance of phosphatidic acid for this pro-survival effect as phosphatidic acid supplementation fully restores MAPK signaling and partially rescues HeLa cells from choline kinase inhibition. Taken together, these data indicate that the pooling of phosphocholine in cancer cells may be required to provide a ready supply of phosphatidic acid necessary for the feed-forward amplification of cancer survival signaling pathways.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19855431</pmid><doi>10.1038/onc.2009.317</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Oncogene, 2010-01, Vol.29 (1), p.139-149 |
| issn | 0950-9232 1476-5594 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Apoptosis Biochemistry Biological and medical sciences Blotting, Western Cancer Care and treatment Cell Biology Cell Line, Transformed Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular signal transduction Choline Kinase - genetics Choline Kinase - metabolism Enzyme inhibitors Female Fundamental and applied biological sciences. Psychology Genetic aspects Genetics Health aspects HeLa Cells Human Genetics Humans Internal Medicine Lipids Magnetic Resonance Spectroscopy Medicine Medicine & Public Health Mice Mice, Nude Mitogen-Activated Protein Kinases - metabolism Molecular and cellular biology Neoplasms, Experimental - genetics Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Oncology original-article Phosphatidic Acids - metabolism Phosphatidylcholines - metabolism Phosphatidylinositol 3-Kinases - metabolism Phosphorylcholine - metabolism Physiological aspects Protein kinases Proto-Oncogene Proteins c-akt - metabolism ras Proteins - genetics ras Proteins - metabolism RNA Interference Signal Transduction Survival Analysis Transplantation, Heterologous Tumor Burden |
| title | Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T07%3A58%3A26IST&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=Selective%20inhibition%20of%20choline%20kinase%20simultaneously%20attenuates%20MAPK%20and%20PI3K/AKT%20signaling&rft.jtitle=Oncogene&rft.au=Yalcin,%20A&rft.date=2010-01-07&rft.volume=29&rft.issue=1&rft.spage=139&rft.epage=149&rft.pages=139-149&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2009.317&rft_dat=%3Cgale_proqu%3EA216631149%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=227340169&rft_id=info:pmid/19855431&rft_galeid=A216631149&rfr_iscdi=true |