Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells
We have analyzed the effects of fluvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in mevalonate synthesis, on human NK cell-mediated anti-tumor cytolysis. Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein...
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| description | We have analyzed the effects of fluvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in mevalonate synthesis, on human NK cell-mediated anti-tumor cytolysis. Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein (GTP) RhoA and the consequent actin redistribution induced by ligation of LFA1 involved in NK-tumor target cell adhesion. Also, fluvastatin reduced ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcγRIIIA (CD16), NKG2D and DNAM1. Cytolysis of tumor targets was inhibited up to 90% when NK cells were cultured with fluvastatin by affecting i) receptor-mediated increase of the intracellular free calcium concentration, ii) activation of akt1/PKB and iii) perforin and granzyme release. Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16-mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably, fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to fluvastatin. Moreover, TNFα secretion triggered in NK cells upon incubation with tumor target cells or engagement of NKG2D receptor was not impaired in fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcγRIIIA engagement with the humanized monoclonal antibody rituximab or trastuzumab was only marginally affected in fluvastatin-treated NK cells. Altogether these findings suggest that interference with mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and granzyme but not FasL- and TNFα-mediated cytotoxicity. |
| doi_str_mv | 10.1371/journal.pone.0062932 |
| format | Article |
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Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein (GTP) RhoA and the consequent actin redistribution induced by ligation of LFA1 involved in NK-tumor target cell adhesion. Also, fluvastatin reduced ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcγRIIIA (CD16), NKG2D and DNAM1. Cytolysis of tumor targets was inhibited up to 90% when NK cells were cultured with fluvastatin by affecting i) receptor-mediated increase of the intracellular free calcium concentration, ii) activation of akt1/PKB and iii) perforin and granzyme release. Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16-mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably, fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to fluvastatin. Moreover, TNFα secretion triggered in NK cells upon incubation with tumor target cells or engagement of NKG2D receptor was not impaired in fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcγRIIIA engagement with the humanized monoclonal antibody rituximab or trastuzumab was only marginally affected in fluvastatin-treated NK cells. Altogether these findings suggest that interference with mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and granzyme but not FasL- and TNFα-mediated cytotoxicity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0062932</identifier><identifier>PMID: 23667543</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actin ; Actins - metabolism ; Activation ; AKT1 protein ; Angiogenesis ; Antibodies, Monoclonal - immunology ; Antibody-Dependent Cell Cytotoxicity - drug effects ; Biology ; Calcium ; Calcium (intracellular) ; Calcium - metabolism ; Calcium content ; Cancer therapies ; Cancer treatment ; CD16 antigen ; Cell adhesion ; Cell growth ; Cell Line, Tumor ; Cholesterol ; Cloning ; Coenzyme A ; Cytolysis ; Cytoskeleton ; Cytotoxicity ; Degranulation ; Enzyme Activation - drug effects ; Enzymes ; Fas Ligand Protein - metabolism ; FasL protein ; Fatty Acids, Monounsaturated - pharmacology ; Fc receptors ; Fluvastatin ; G(M1) Ganglioside - metabolism ; Granzymes - metabolism ; Guanosine triphosphate ; Humans ; Immunoglobulins ; Indoles - pharmacology ; Intracellular Space - drug effects ; Intracellular Space - metabolism ; Killer cells ; Killer Cells, Natural - cytology ; Killer Cells, Natural - drug effects ; Killer Cells, Natural - immunology ; Killer Cells, Natural - metabolism ; Kinases ; Leukemia ; Ligands ; Lymphocyte Function-Associated Antigen-1 - metabolism ; Lymphocyte receptors ; Lymphoma ; Medical research ; Medicine ; Membrane Microdomains - drug effects ; Membrane Microdomains - metabolism ; Mevalonate pathway ; Mevalonic acid ; Mevalonic Acid - metabolism ; Monoclonal antibodies ; Muscle proteins ; Natural killer cells ; NKG2 antigen ; Oncology ; Perforin ; Perforin - metabolism ; Potassium channels (inwardly-rectifying) ; Protein binding ; Proto-Oncogene Proteins c-akt - metabolism ; Rafts ; Receptors ; Receptors, IgG - metabolism ; Reductase ; rhoA GTP-Binding Protein - metabolism ; RhoA protein ; Rituximab ; Secretion ; Synthesis ; Targeted cancer therapy ; Toxicity ; Trastuzumab ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2013-05, Vol.8 (5), p.e62932</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Poggi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Poggi et al 2013 Poggi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-411d0d27780d5a01e5d3bc9f19a7dbcf988c0f67dbfaf4167ee0f9ce8f5cc91d3</citedby><cites>FETCH-LOGICAL-c692t-411d0d27780d5a01e5d3bc9f19a7dbcf988c0f67dbfaf4167ee0f9ce8f5cc91d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646988/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646988/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23667543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bobé, Pierre</contributor><creatorcontrib>Poggi, Alessandro</creatorcontrib><creatorcontrib>Boero, Silvia</creatorcontrib><creatorcontrib>Musso, Alessandra</creatorcontrib><creatorcontrib>Zocchi, Maria Raffaella</creatorcontrib><title>Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We have analyzed the effects of fluvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in mevalonate synthesis, on human NK cell-mediated anti-tumor cytolysis. Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein (GTP) RhoA and the consequent actin redistribution induced by ligation of LFA1 involved in NK-tumor target cell adhesion. Also, fluvastatin reduced ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcγRIIIA (CD16), NKG2D and DNAM1. Cytolysis of tumor targets was inhibited up to 90% when NK cells were cultured with fluvastatin by affecting i) receptor-mediated increase of the intracellular free calcium concentration, ii) activation of akt1/PKB and iii) perforin and granzyme release. Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16-mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably, fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to fluvastatin. Moreover, TNFα secretion triggered in NK cells upon incubation with tumor target cells or engagement of NKG2D receptor was not impaired in fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcγRIIIA engagement with the humanized monoclonal antibody rituximab or trastuzumab was only marginally affected in fluvastatin-treated NK cells. Altogether these findings suggest that interference with mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and granzyme but not FasL- and TNFα-mediated cytotoxicity.</description><subject>Actin</subject><subject>Actins - metabolism</subject><subject>Activation</subject><subject>AKT1 protein</subject><subject>Angiogenesis</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibody-Dependent Cell Cytotoxicity - drug effects</subject><subject>Biology</subject><subject>Calcium</subject><subject>Calcium (intracellular)</subject><subject>Calcium - metabolism</subject><subject>Calcium content</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>CD16 antigen</subject><subject>Cell adhesion</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cholesterol</subject><subject>Cloning</subject><subject>Coenzyme A</subject><subject>Cytolysis</subject><subject>Cytoskeleton</subject><subject>Cytotoxicity</subject><subject>Degranulation</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzymes</subject><subject>Fas Ligand Protein - metabolism</subject><subject>FasL protein</subject><subject>Fatty Acids, Monounsaturated - pharmacology</subject><subject>Fc receptors</subject><subject>Fluvastatin</subject><subject>G(M1) Ganglioside - metabolism</subject><subject>Granzymes - metabolism</subject><subject>Guanosine triphosphate</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Indoles - pharmacology</subject><subject>Intracellular Space - drug effects</subject><subject>Intracellular Space - metabolism</subject><subject>Killer cells</subject><subject>Killer Cells, Natural - cytology</subject><subject>Killer Cells, Natural - drug effects</subject><subject>Killer Cells, Natural - immunology</subject><subject>Killer Cells, Natural - metabolism</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Ligands</subject><subject>Lymphocyte Function-Associated Antigen-1 - metabolism</subject><subject>Lymphocyte receptors</subject><subject>Lymphoma</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Membrane Microdomains - drug effects</subject><subject>Membrane Microdomains - metabolism</subject><subject>Mevalonate pathway</subject><subject>Mevalonic acid</subject><subject>Mevalonic Acid - metabolism</subject><subject>Monoclonal antibodies</subject><subject>Muscle proteins</subject><subject>Natural killer cells</subject><subject>NKG2 antigen</subject><subject>Oncology</subject><subject>Perforin</subject><subject>Perforin - metabolism</subject><subject>Potassium channels (inwardly-rectifying)</subject><subject>Protein binding</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rafts</subject><subject>Receptors</subject><subject>Receptors, IgG - metabolism</subject><subject>Reductase</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>RhoA protein</subject><subject>Rituximab</subject><subject>Secretion</subject><subject>Synthesis</subject><subject>Targeted cancer therapy</subject><subject>Toxicity</subject><subject>Trastuzumab</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNklGLEzEUhQdR3HX1H4gGBMGH1mQyk5l5EZbFarHsgrv6Gu5kbtqUdNJNMtXFP29qu0sLCpKHhJvvnJtcTpa9ZHTMeMXeL93ge7DjtetxTKnIG54_yk5Z2kYip_zxwfkkexbCktKS10I8zU5yLkRVFvw0-3WNFlU0GyTeWSROkxVuwLoeIpI1xMUPuCOmJx7ng4Vo-jlZo9fOp1o7RNK7SCYQZgT6jtxcTsCuF5BoixBwK1wMK-jJJcTBgyVfjLXoiUJrw_PsiQYb8MV-P8u-TT7eXHweza4-TS_OZyMlmjyOCsY62uVVVdOuBMqw7HirGs0aqLpW6aauFdUinTXogokKkepGYa1LpRrW8bPs9c53bV2Q-7kFyXhJG1bUgiViuiM6B0u59mYF_k46MPJPwfm5BB-NsihrxQU2uisVZQW0BTCGwDpotSp03m67fdh3G9oVdgr7mD5-ZHp805uFnLuN5KIQ6S_J4M3ewLvbAUP8x5P31BzSq0yvXTJTKxOUPC-qmje8yXmixn-h0upwZVRKjjapfiR4dyRITMSfcQ5DCHJ6_fX_2avvx-zbA3aBYOMiODtE4_pwDBY7UHkXgkf9MDlG5Tb499OQ2-DLffCT7NXh1B9E90nnvwGT2wEb</recordid><startdate>20130507</startdate><enddate>20130507</enddate><creator>Poggi, Alessandro</creator><creator>Boero, Silvia</creator><creator>Musso, Alessandra</creator><creator>Zocchi, Maria Raffaella</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130507</creationdate><title>Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells</title><author>Poggi, Alessandro ; Boero, Silvia ; Musso, Alessandra ; Zocchi, Maria Raffaella</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-411d0d27780d5a01e5d3bc9f19a7dbcf988c0f67dbfaf4167ee0f9ce8f5cc91d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Actin</topic><topic>Actins - 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metabolism</topic><topic>Guanosine triphosphate</topic><topic>Humans</topic><topic>Immunoglobulins</topic><topic>Indoles - pharmacology</topic><topic>Intracellular Space - drug effects</topic><topic>Intracellular Space - metabolism</topic><topic>Killer cells</topic><topic>Killer Cells, Natural - cytology</topic><topic>Killer Cells, Natural - drug effects</topic><topic>Killer Cells, Natural - immunology</topic><topic>Killer Cells, Natural - metabolism</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Ligands</topic><topic>Lymphocyte Function-Associated Antigen-1 - metabolism</topic><topic>Lymphocyte receptors</topic><topic>Lymphoma</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Membrane Microdomains - drug effects</topic><topic>Membrane Microdomains - metabolism</topic><topic>Mevalonate pathway</topic><topic>Mevalonic acid</topic><topic>Mevalonic Acid - metabolism</topic><topic>Monoclonal antibodies</topic><topic>Muscle proteins</topic><topic>Natural killer cells</topic><topic>NKG2 antigen</topic><topic>Oncology</topic><topic>Perforin</topic><topic>Perforin - metabolism</topic><topic>Potassium channels (inwardly-rectifying)</topic><topic>Protein binding</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rafts</topic><topic>Receptors</topic><topic>Receptors, IgG - metabolism</topic><topic>Reductase</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>RhoA protein</topic><topic>Rituximab</topic><topic>Secretion</topic><topic>Synthesis</topic><topic>Targeted cancer therapy</topic><topic>Toxicity</topic><topic>Trastuzumab</topic><topic>Tumor necrosis factor</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Poggi, Alessandro</creatorcontrib><creatorcontrib>Boero, Silvia</creatorcontrib><creatorcontrib>Musso, Alessandra</creatorcontrib><creatorcontrib>Zocchi, Maria Raffaella</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Poggi, Alessandro</au><au>Boero, Silvia</au><au>Musso, Alessandra</au><au>Zocchi, Maria Raffaella</au><au>Bobé, Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-05-07</date><risdate>2013</risdate><volume>8</volume><issue>5</issue><spage>e62932</spage><pages>e62932-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We have analyzed the effects of fluvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in mevalonate synthesis, on human NK cell-mediated anti-tumor cytolysis. Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein (GTP) RhoA and the consequent actin redistribution induced by ligation of LFA1 involved in NK-tumor target cell adhesion. Also, fluvastatin reduced ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcγRIIIA (CD16), NKG2D and DNAM1. Cytolysis of tumor targets was inhibited up to 90% when NK cells were cultured with fluvastatin by affecting i) receptor-mediated increase of the intracellular free calcium concentration, ii) activation of akt1/PKB and iii) perforin and granzyme release. Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16-mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably, fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to fluvastatin. Moreover, TNFα secretion triggered in NK cells upon incubation with tumor target cells or engagement of NKG2D receptor was not impaired in fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcγRIIIA engagement with the humanized monoclonal antibody rituximab or trastuzumab was only marginally affected in fluvastatin-treated NK cells. Altogether these findings suggest that interference with mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and granzyme but not FasL- and TNFα-mediated cytotoxicity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23667543</pmid><doi>10.1371/journal.pone.0062932</doi><tpages>e62932</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-05, Vol.8 (5), p.e62932 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1350914861 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Actin Actins - metabolism Activation AKT1 protein Angiogenesis Antibodies, Monoclonal - immunology Antibody-Dependent Cell Cytotoxicity - drug effects Biology Calcium Calcium (intracellular) Calcium - metabolism Calcium content Cancer therapies Cancer treatment CD16 antigen Cell adhesion Cell growth Cell Line, Tumor Cholesterol Cloning Coenzyme A Cytolysis Cytoskeleton Cytotoxicity Degranulation Enzyme Activation - drug effects Enzymes Fas Ligand Protein - metabolism FasL protein Fatty Acids, Monounsaturated - pharmacology Fc receptors Fluvastatin G(M1) Ganglioside - metabolism Granzymes - metabolism Guanosine triphosphate Humans Immunoglobulins Indoles - pharmacology Intracellular Space - drug effects Intracellular Space - metabolism Killer cells Killer Cells, Natural - cytology Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Kinases Leukemia Ligands Lymphocyte Function-Associated Antigen-1 - metabolism Lymphocyte receptors Lymphoma Medical research Medicine Membrane Microdomains - drug effects Membrane Microdomains - metabolism Mevalonate pathway Mevalonic acid Mevalonic Acid - metabolism Monoclonal antibodies Muscle proteins Natural killer cells NKG2 antigen Oncology Perforin Perforin - metabolism Potassium channels (inwardly-rectifying) Protein binding Proto-Oncogene Proteins c-akt - metabolism Rafts Receptors Receptors, IgG - metabolism Reductase rhoA GTP-Binding Protein - metabolism RhoA protein Rituximab Secretion Synthesis Targeted cancer therapy Toxicity Trastuzumab Tumor necrosis factor Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α |
| title | Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells |
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