Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy
The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (49), p.19569-19574 |
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| creator | Barceló-Coblijn, Gwendolyn Martin, Maria Laura de Almeida, Rodrigo F. M Noguera-Salvà, Maria Antònia Marcilla-Etxenike, Amaia Guardiola-Serrano, Francisca Lüth, Anja Kleuser, Burhard Halver, John E Escribá, Pablo V |
| description | The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells. |
| doi_str_mv | 10.1073/pnas.1115484108 |
| format | Article |
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M ; Noguera-Salvà, Maria Antònia ; Marcilla-Etxenike, Amaia ; Guardiola-Serrano, Francisca ; Lüth, Anja ; Kleuser, Burhard ; Halver, John E ; Escribá, Pablo V</creator><creatorcontrib>Barceló-Coblijn, Gwendolyn ; Martin, Maria Laura ; de Almeida, Rodrigo F. M ; Noguera-Salvà, Maria Antònia ; Marcilla-Etxenike, Amaia ; Guardiola-Serrano, Francisca ; Lüth, Anja ; Kleuser, Burhard ; Halver, John E ; Escribá, Pablo V</creatorcontrib><description>The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1115484108</identifier><identifier>PMID: 22106271</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>adverse effects ; Apoptosis ; Apoptosis - drug effects ; autophagy ; Biological Sciences ; Bridged-Ring Compounds - pharmacology ; Cancer ; Cell cycle ; Cell Cycle Checkpoints - drug effects ; cell differentiation ; Cell Differentiation - drug effects ; Cell Line, Tumor ; Cell lines ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; Cell membranes ; Cell Survival - drug effects ; Cell Transformation, Neoplastic ; Cells ; fas Receptor - metabolism ; Fatty acids ; Gene Expression Regulation, Enzymologic ; Glioma - genetics ; Glioma - metabolism ; Glioma - pathology ; Humans ; Immunoblotting ; Jurkat Cells ; Lipids ; mechanism of action ; Membrane Microdomains - drug effects ; Membrane Microdomains - metabolism ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membranes ; neoplastic cell transformation ; Nerve Tissue Proteins - antagonists & inhibitors ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; nitric oxide synthase ; Oleic Acids - pharmacology ; phosphatidylcholines ; Phosphodiesterase Inhibitors - pharmacology ; Phospholipids ; Physical Sciences ; plasma membrane ; Proteins ; Rafts ; ras Proteins - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; sphingomyelins ; Sphingomyelins - metabolism ; T lymphocytes ; therapeutics ; Thiones - pharmacology ; Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors ; Transferases (Other Substituted Phosphate Groups) - genetics ; Transferases (Other Substituted Phosphate Groups) - metabolism ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-12, Vol.108 (49), p.19569-19574</ispartof><rights>copyright © 1993—2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 6, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c622t-3e25eee862293a1216a4de164b1ae88353d71de254c7f0123646c2889e3f21993</citedby><cites>FETCH-LOGICAL-c622t-3e25eee862293a1216a4de164b1ae88353d71de254c7f0123646c2889e3f21993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/49.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23059535$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23059535$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22106271$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barceló-Coblijn, Gwendolyn</creatorcontrib><creatorcontrib>Martin, Maria Laura</creatorcontrib><creatorcontrib>de Almeida, Rodrigo F. M</creatorcontrib><creatorcontrib>Noguera-Salvà, Maria Antònia</creatorcontrib><creatorcontrib>Marcilla-Etxenike, Amaia</creatorcontrib><creatorcontrib>Guardiola-Serrano, Francisca</creatorcontrib><creatorcontrib>Lüth, Anja</creatorcontrib><creatorcontrib>Kleuser, Burhard</creatorcontrib><creatorcontrib>Halver, John E</creatorcontrib><creatorcontrib>Escribá, Pablo V</creatorcontrib><title>Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.</description><subject>adverse effects</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>autophagy</subject><subject>Biological Sciences</subject><subject>Bridged-Ring Compounds - pharmacology</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>cell differentiation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>Cell membranes</subject><subject>Cell Survival - drug effects</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cells</subject><subject>fas Receptor - metabolism</subject><subject>Fatty acids</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Glioma - genetics</subject><subject>Glioma - metabolism</subject><subject>Glioma - pathology</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Jurkat Cells</subject><subject>Lipids</subject><subject>mechanism of action</subject><subject>Membrane Microdomains - drug effects</subject><subject>Membrane Microdomains - metabolism</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Membranes</subject><subject>neoplastic cell transformation</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>nitric oxide synthase</subject><subject>Oleic Acids - pharmacology</subject><subject>phosphatidylcholines</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phospholipids</subject><subject>Physical Sciences</subject><subject>plasma membrane</subject><subject>Proteins</subject><subject>Rafts</subject><subject>ras Proteins - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>sphingomyelins</subject><subject>Sphingomyelins - metabolism</subject><subject>T lymphocytes</subject><subject>therapeutics</subject><subject>Thiones - pharmacology</subject><subject>Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors</subject><subject>Transferases (Other Substituted Phosphate Groups) - genetics</subject><subject>Transferases (Other Substituted Phosphate Groups) - metabolism</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkk1v1DAQhi0EosvCmRNgcSqHtB7bcexLJVRRQCrisPRsuYmT9SqxFzuLyJF_jtNdupQLJ8szz7x65wOhl0DOgFTsfOtNOgOAkksORD5CCyAKCsEVeYwWhNCqkJzyE_QspQ0hRJWSPEUnlAIRtIIF-rXarp3vwjDZ3nlsfIPTg0ia_Lg2yeLT1ZfVO5wj49riwfSu88aPeIzGpzbEwYwueBxa3PUuDAbXtu_TnWCuocV6amL4OYXeuhqb2jWzTjTb6Tl60po-2ReHd4lurj58u_xUXH_9-Pny_XVRC0rHgllaWmtl_ihmgIIwvLEg-C0YKyUrWVNBkyFeVy0BygQXNZVSWdZSUIot0cVed7u7HWxTW5-t93ob3WDipINx-mHGu7Xuwg_NKIdKVlng9CAQw_edTaMeXJq7NN6GXdIgBCupkor_H80LAMZFtrlEb_9BN2EXfZ6EVkRxpUogGTrfQ3UMKUXb3tsGoudD0PMh6OMh5IrXf3d7z__ZfAbwAZgrj3JSc6VBlWKe2Ks9skljiEcJRkpV5oEv0Zt9vjVBmy66pG9WlAAnBKqqJJz9BhD1zPk</recordid><startdate>20111206</startdate><enddate>20111206</enddate><creator>Barceló-Coblijn, Gwendolyn</creator><creator>Martin, Maria Laura</creator><creator>de Almeida, Rodrigo F. 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M ; Noguera-Salvà, Maria Antònia ; Marcilla-Etxenike, Amaia ; Guardiola-Serrano, Francisca ; Lüth, Anja ; Kleuser, Burhard ; Halver, John E ; Escribá, Pablo V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c622t-3e25eee862293a1216a4de164b1ae88353d71de254c7f0123646c2889e3f21993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>adverse effects</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>autophagy</topic><topic>Biological Sciences</topic><topic>Bridged-Ring Compounds - pharmacology</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>cell differentiation</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>Cell membranes</topic><topic>Cell Survival - drug effects</topic><topic>Cell Transformation, Neoplastic</topic><topic>Cells</topic><topic>fas Receptor - metabolism</topic><topic>Fatty acids</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Glioma - genetics</topic><topic>Glioma - metabolism</topic><topic>Glioma - pathology</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Jurkat Cells</topic><topic>Lipids</topic><topic>mechanism of action</topic><topic>Membrane Microdomains - drug effects</topic><topic>Membrane Microdomains - metabolism</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Membranes</topic><topic>neoplastic cell transformation</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>nitric oxide synthase</topic><topic>Oleic Acids - pharmacology</topic><topic>phosphatidylcholines</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phospholipids</topic><topic>Physical Sciences</topic><topic>plasma membrane</topic><topic>Proteins</topic><topic>Rafts</topic><topic>ras Proteins - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>sphingomyelins</topic><topic>Sphingomyelins - metabolism</topic><topic>T lymphocytes</topic><topic>therapeutics</topic><topic>Thiones - pharmacology</topic><topic>Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors</topic><topic>Transferases (Other Substituted Phosphate Groups) - genetics</topic><topic>Transferases (Other Substituted Phosphate Groups) - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barceló-Coblijn, Gwendolyn</creatorcontrib><creatorcontrib>Martin, Maria Laura</creatorcontrib><creatorcontrib>de Almeida, Rodrigo F. 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M</au><au>Noguera-Salvà, Maria Antònia</au><au>Marcilla-Etxenike, Amaia</au><au>Guardiola-Serrano, Francisca</au><au>Lüth, Anja</au><au>Kleuser, Burhard</au><au>Halver, John E</au><au>Escribá, Pablo V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-12-06</date><risdate>2011</risdate><volume>108</volume><issue>49</issue><spage>19569</spage><epage>19574</epage><pages>19569-19574</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>22106271</pmid><doi>10.1073/pnas.1115484108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | adverse effects Apoptosis Apoptosis - drug effects autophagy Biological Sciences Bridged-Ring Compounds - pharmacology Cancer Cell cycle Cell Cycle Checkpoints - drug effects cell differentiation Cell Differentiation - drug effects Cell Line, Tumor Cell lines Cell Membrane - drug effects Cell Membrane - metabolism Cell membranes Cell Survival - drug effects Cell Transformation, Neoplastic Cells fas Receptor - metabolism Fatty acids Gene Expression Regulation, Enzymologic Glioma - genetics Glioma - metabolism Glioma - pathology Humans Immunoblotting Jurkat Cells Lipids mechanism of action Membrane Microdomains - drug effects Membrane Microdomains - metabolism Membrane Proteins - antagonists & inhibitors Membrane Proteins - genetics Membrane Proteins - metabolism Membranes neoplastic cell transformation Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism nitric oxide synthase Oleic Acids - pharmacology phosphatidylcholines Phosphodiesterase Inhibitors - pharmacology Phospholipids Physical Sciences plasma membrane Proteins Rafts ras Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction sphingomyelins Sphingomyelins - metabolism T lymphocytes therapeutics Thiones - pharmacology Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors Transferases (Other Substituted Phosphate Groups) - genetics Transferases (Other Substituted Phosphate Groups) - metabolism Tumors |
| title | Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy |
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