Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines
Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide synthase has not been studied in drug-sensitive...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-04, Vol.279 (18), p.18256-18261 |
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| container_title | The Journal of biological chemistry |
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| creator | Grazide, Solène Terrisse, Anne-Dominique Lerouge, Sandra Laurent, Guy Jaffrézou, Jean-Pierre |
| description | Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and
that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide
synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin
(DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell
lines. We now report that inhibition of glucosylceramide synthase using d , l -threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP)
protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased
CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER)
significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease)
were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts,
whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived
CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis
âprotectorâ (GalCER). |
| doi_str_mv | 10.1074/jbc.M314105200 |
| format | Article |
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that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide
synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin
(DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell
lines. We now report that inhibition of glucosylceramide synthase using d , l -threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP)
protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased
CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER)
significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease)
were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts,
whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived
CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis
âprotectorâ (GalCER).</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M314105200</identifier><identifier>PMID: 14766899</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Line, Tumor ; Cytarabine - pharmacology ; Daunorubicin - pharmacology ; Drug Resistance, Neoplasm ; Enzyme Inhibitors - pharmacology ; Glucosyltransferases - antagonists & inhibitors ; Glycosylation ; HL-60 Cells ; Humans ; Leukemia, Myeloid - pathology ; Morpholines - pharmacology ; Protective Agents - pharmacology ; U937 Cells</subject><ispartof>The Journal of biological chemistry, 2004-04, Vol.279 (18), p.18256-18261</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-1da55726e875a61c39885533bd9a04e6783a6ce86213db44f0efd0272e99276b3</citedby><cites>FETCH-LOGICAL-c386t-1da55726e875a61c39885533bd9a04e6783a6ce86213db44f0efd0272e99276b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14766899$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grazide, Solène</creatorcontrib><creatorcontrib>Terrisse, Anne-Dominique</creatorcontrib><creatorcontrib>Lerouge, Sandra</creatorcontrib><creatorcontrib>Laurent, Guy</creatorcontrib><creatorcontrib>Jaffrézou, Jean-Pierre</creatorcontrib><title>Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and
that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide
synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin
(DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell
lines. We now report that inhibition of glucosylceramide synthase using d , l -threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP)
protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased
CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER)
significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease)
were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts,
whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived
CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis
âprotectorâ (GalCER).</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cytarabine - pharmacology</subject><subject>Daunorubicin - pharmacology</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glucosyltransferases - antagonists & inhibitors</subject><subject>Glycosylation</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Leukemia, Myeloid - pathology</subject><subject>Morpholines - pharmacology</subject><subject>Protective Agents - pharmacology</subject><subject>U937 Cells</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1v2zAQhomgQeImWTsWHLrK5YdIkWPgurEBFx3SANkEijpFl0qkIEopPPafV4UD-HDAvcPz3vAQ8omzNWdF_vW18usfkuecKcHYBVlxZmQmFX_-QFaMCZ5Zocw1-ZjSK1smt_yKXPO80NpYuyJ_N8cpDmOcwE_4BnTbNEuisaEP3exjOnYeRtdjDfTxGKbWJaD70GKFE8ZA3YvDkCb6zc0hjnOFHkOGoZ491PR-iMMUEyaKge7m3gV6gPk39OjpBrqOHjBAuiWXjesS3L3fG_L0fftrs8sOPx_2m_tD5qXRU8Zrp1QhNJhCOc29tMYoJWVVW8dy0IWRTnswWnBZV3neMGhqJgoB1opCV_KGrE9__RhTGqEphxF7Nx5Lzsr_LsvFZXl2uRQ-nwrDXPVQn_F3eQvw5QS0-NL-wRHKCqNvoS9FYUtulhVKy394AX3Q</recordid><startdate>20040430</startdate><enddate>20040430</enddate><creator>Grazide, Solène</creator><creator>Terrisse, Anne-Dominique</creator><creator>Lerouge, Sandra</creator><creator>Laurent, Guy</creator><creator>Jaffrézou, Jean-Pierre</creator><general>American Society for Biochemistry and Molecular Biology</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></search><sort><creationdate>20040430</creationdate><title>Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines</title><author>Grazide, Solène ; Terrisse, Anne-Dominique ; Lerouge, Sandra ; Laurent, Guy ; Jaffrézou, Jean-Pierre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-1da55726e875a61c39885533bd9a04e6783a6ce86213db44f0efd0272e99276b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cytarabine - pharmacology</topic><topic>Daunorubicin - pharmacology</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glucosyltransferases - antagonists & inhibitors</topic><topic>Glycosylation</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Leukemia, Myeloid - pathology</topic><topic>Morpholines - pharmacology</topic><topic>Protective Agents - pharmacology</topic><topic>U937 Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grazide, Solène</creatorcontrib><creatorcontrib>Terrisse, Anne-Dominique</creatorcontrib><creatorcontrib>Lerouge, Sandra</creatorcontrib><creatorcontrib>Laurent, Guy</creatorcontrib><creatorcontrib>Jaffrézou, Jean-Pierre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grazide, Solène</au><au>Terrisse, Anne-Dominique</au><au>Lerouge, Sandra</au><au>Laurent, Guy</au><au>Jaffrézou, Jean-Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-04-30</date><risdate>2004</risdate><volume>279</volume><issue>18</issue><spage>18256</spage><epage>18261</epage><pages>18256-18261</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and
that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide
synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin
(DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell
lines. We now report that inhibition of glucosylceramide synthase using d , l -threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP)
protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased
CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER)
significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease)
were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts,
whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived
CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis
âprotectorâ (GalCER).</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>14766899</pmid><doi>10.1074/jbc.M314105200</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Cytarabine - pharmacology Daunorubicin - pharmacology Drug Resistance, Neoplasm Enzyme Inhibitors - pharmacology Glucosyltransferases - antagonists & inhibitors Glycosylation HL-60 Cells Humans Leukemia, Myeloid - pathology Morpholines - pharmacology Protective Agents - pharmacology U937 Cells |
| title | Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines |
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