Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells
Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2012-09, Vol.72 (17), p.4562-4573 |
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| creator | SURGET, Sylvanie CHIRON, David GOMEZ-BOUGIE, Patricia DESCAMPS, Géraldine MENORET, Emmanuelle BATAILLE, Régis MOREAU, Philippe LE GOUILL, Steven AMIOT, Martine PELLAT-DECEUNYNCK, Catherine |
| description | Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab. TP53 wild-type myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both nongenotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increased DR5 expression only in TP53 wild-type cells and synergistically increased lexatumumab efficiency yet did not increase DR4 expression, nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin-3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin-3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin-3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5 but not DR4 and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy. |
| doi_str_mv | 10.1158/0008-5472.CAN-12-0487 |
| format | Article |
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Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab. TP53 wild-type myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both nongenotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increased DR5 expression only in TP53 wild-type cells and synergistically increased lexatumumab efficiency yet did not increase DR4 expression, nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin-3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin-3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin-3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5 but not DR4 and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-12-0487</identifier><identifier>PMID: 22738917</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antibodies, Monoclonal - pharmacology ; Antibodies, Monoclonal - toxicity ; Antineoplastic agents ; Biological and medical sciences ; Caspase 8 - metabolism ; Cell Death - drug effects ; Cell Death - genetics ; Cell Line, Tumor ; Chromosome Deletion ; Chromosomes, Human, Pair 17 ; Drug Resistance, Neoplasm - genetics ; Enzyme Activation - drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Silencing ; Hematologic and hematopoietic diseases ; Humans ; Imidazoles - pharmacology ; Immunodeficiencies. Immunoglobulinopathies ; Immunoglobulinopathies ; Immunopathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Multiple Myeloma - genetics ; Multiple Myeloma - metabolism ; Pharmacology. Drug treatments ; Piperazines - pharmacology ; Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors ; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Stress, Physiological - drug effects ; Stress, Physiological - genetics ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2012-09, Vol.72 (17), p.4562-4573</ispartof><rights>2015 INIST-CNRS</rights><rights>2012 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-3f7e24b0db68664b789a52a4cdba892904a167d9be70d0cbc314a97bdffc256a3</citedby><cites>FETCH-LOGICAL-c386t-3f7e24b0db68664b789a52a4cdba892904a167d9be70d0cbc314a97bdffc256a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26354535$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22738917$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SURGET, Sylvanie</creatorcontrib><creatorcontrib>CHIRON, David</creatorcontrib><creatorcontrib>GOMEZ-BOUGIE, Patricia</creatorcontrib><creatorcontrib>DESCAMPS, Géraldine</creatorcontrib><creatorcontrib>MENORET, Emmanuelle</creatorcontrib><creatorcontrib>BATAILLE, Régis</creatorcontrib><creatorcontrib>MOREAU, Philippe</creatorcontrib><creatorcontrib>LE GOUILL, Steven</creatorcontrib><creatorcontrib>AMIOT, Martine</creatorcontrib><creatorcontrib>PELLAT-DECEUNYNCK, Catherine</creatorcontrib><title>Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab. TP53 wild-type myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both nongenotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increased DR5 expression only in TP53 wild-type cells and synergistically increased lexatumumab efficiency yet did not increase DR4 expression, nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin-3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin-3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin-3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5 but not DR4 and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy.</description><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal - toxicity</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Caspase 8 - metabolism</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - genetics</subject><subject>Cell Line, Tumor</subject><subject>Chromosome Deletion</subject><subject>Chromosomes, Human, Pair 17</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Enzyme Activation - drug effects</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Silencing</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Immunodeficiencies. Immunoglobulinopathies</subject><subject>Immunoglobulinopathies</subject><subject>Immunopathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - pharmacology</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>Stress, Physiological - drug effects</subject><subject>Stress, Physiological - genetics</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkFtLwzAYhoMobk5_gpIbwYt15tikl6ObOpgKQ69DkqZa6WE2rbB_b8rmvPr44Hm_wwPANUYzjLm8RwjJiDNBZun8JcIkQkyKEzDGnMpIMMZPwfjIjMCF91-h5RjxczAiRFCZYDEGy9SVJVw43X3Cn0LDxYZPoek7WDddaNgUrjzcuI--1J3LoNnBLaewqOHzzpVNpeGQ95fgLNeld1eHOgHvD8u39Clavz6u0vk6slTGXURz4QgzKDOxjGNmhEw0J5rZzGiZkAQxjWORJcYJlCFrLMVMJ8JkeW4JjzWdgLv93G3bfPfOd6oqvA0X6No1vVcYUSElp-G9CeB71LaN963L1bYtKt3uAqQGg2qwowY7KhhUmKjBYMjdHFb0pnLZMfWnLAC3B0B7q8u81bUt_D8XU8445fQXiTB1vg</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>SURGET, Sylvanie</creator><creator>CHIRON, David</creator><creator>GOMEZ-BOUGIE, Patricia</creator><creator>DESCAMPS, Géraldine</creator><creator>MENORET, Emmanuelle</creator><creator>BATAILLE, Régis</creator><creator>MOREAU, Philippe</creator><creator>LE GOUILL, Steven</creator><creator>AMIOT, Martine</creator><creator>PELLAT-DECEUNYNCK, Catherine</creator><general>American Association for Cancer Research</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>7X8</scope></search><sort><creationdate>20120901</creationdate><title>Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells</title><author>SURGET, Sylvanie ; CHIRON, David ; GOMEZ-BOUGIE, Patricia ; DESCAMPS, Géraldine ; MENORET, Emmanuelle ; BATAILLE, Régis ; MOREAU, Philippe ; LE GOUILL, Steven ; AMIOT, Martine ; PELLAT-DECEUNYNCK, Catherine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-3f7e24b0db68664b789a52a4cdba892904a167d9be70d0cbc314a97bdffc256a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antibodies, Monoclonal - toxicity</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Caspase 8 - metabolism</topic><topic>Cell Death - drug effects</topic><topic>Cell Death - genetics</topic><topic>Cell Line, Tumor</topic><topic>Chromosome Deletion</topic><topic>Chromosomes, Human, Pair 17</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Enzyme Activation - drug effects</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Silencing</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Immunodeficiencies. Immunoglobulinopathies</topic><topic>Immunoglobulinopathies</topic><topic>Immunopathology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Multiple Myeloma - genetics</topic><topic>Multiple Myeloma - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - pharmacology</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>Stress, Physiological - drug effects</topic><topic>Stress, Physiological - genetics</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SURGET, Sylvanie</creatorcontrib><creatorcontrib>CHIRON, David</creatorcontrib><creatorcontrib>GOMEZ-BOUGIE, Patricia</creatorcontrib><creatorcontrib>DESCAMPS, Géraldine</creatorcontrib><creatorcontrib>MENORET, Emmanuelle</creatorcontrib><creatorcontrib>BATAILLE, Régis</creatorcontrib><creatorcontrib>MOREAU, Philippe</creatorcontrib><creatorcontrib>LE GOUILL, Steven</creatorcontrib><creatorcontrib>AMIOT, Martine</creatorcontrib><creatorcontrib>PELLAT-DECEUNYNCK, Catherine</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SURGET, Sylvanie</au><au>CHIRON, David</au><au>GOMEZ-BOUGIE, Patricia</au><au>DESCAMPS, Géraldine</au><au>MENORET, Emmanuelle</au><au>BATAILLE, Régis</au><au>MOREAU, Philippe</au><au>LE GOUILL, Steven</au><au>AMIOT, Martine</au><au>PELLAT-DECEUNYNCK, Catherine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>72</volume><issue>17</issue><spage>4562</spage><epage>4573</epage><pages>4562-4573</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Myeloma cells are sensitive to TRAIL through the two death receptors DR4 and DR5. Because p53 directly modulates expression of death receptors, we investigated here whether p53 can modulate myeloma sensitivity to TRAIL. We found that p53 affects the sensitivity of myeloma cells to the DR5 agonistic human antibody lexatumumab but not the DR4 antibody mapatumumab. TP53 wild-type myeloma cells overexpressed DR5 in correlation with sensitivity to lexatumumab. Both nongenotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increased DR5 expression only in TP53 wild-type cells and synergistically increased lexatumumab efficiency yet did not increase DR4 expression, nor sensitivity to mapatumumab. Silencing of p53 strongly decreased DR5 expression and induced resistance to nutlin-3a and lexatumumab but did not modulate DR4 expression or sensitivity to mapatumumab. Increase of lexatumumab efficiency induced by nutlin-3a was related to a p53-dependent increase of DR5 expression. In primary myeloma cells, nutlin-3a increased DR5 expression and lexatumumab efficiency but did not increase mapatumumab efficiency. Taken together, our findings indicate that p53 controls the sensitivity of myeloma through DR5 but not DR4 and suggest that a subset of patients with multiple myeloma may benefit from DR5 therapy.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>22738917</pmid><doi>10.1158/0008-5472.CAN-12-0487</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - toxicity Antineoplastic agents Biological and medical sciences Caspase 8 - metabolism Cell Death - drug effects Cell Death - genetics Cell Line, Tumor Chromosome Deletion Chromosomes, Human, Pair 17 Drug Resistance, Neoplasm - genetics Enzyme Activation - drug effects Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Gene Silencing Hematologic and hematopoietic diseases Humans Imidazoles - pharmacology Immunodeficiencies. Immunoglobulinopathies Immunoglobulinopathies Immunopathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Multiple Myeloma - genetics Multiple Myeloma - metabolism Pharmacology. Drug treatments Piperazines - pharmacology Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Stress, Physiological - drug effects Stress, Physiological - genetics Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors |
| title | Cell Death via DR5, but not DR4, Is Regulated by p53 in Myeloma Cells |
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