Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E
Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic deat...
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| Veröffentlicht in: | International journal of oncology 2015-02, Vol.46 (2), p.860-870 |
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| creator | ZISMANOV, VICTORIA ATTAR-SCHNEIDER, OSHRAT LISHNER, MICHAEL AIZENFELD, RACHEL HEFFEZ MATALON, SHELLY TARTAKOVER DRUCKER, LIAT |
| description | Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin-induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c-Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti-viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti-MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic. |
| doi_str_mv | 10.3892/ijo.2014.2774 |
| format | Article |
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Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin-induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c-Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti-viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti-MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.2014.2774</identifier><identifier>PMID: 25422161</identifier><language>eng</language><publisher>Greece: D.A. Spandidos</publisher><subject>Akt ; Antibiotics ; Antiviral agents ; Antiviral drugs ; Autophagy - drug effects ; Bone marrow ; CD81N1 ; CD82N1 ; Cell Line, Tumor ; Cyclin D1 - biosynthesis ; Drug therapy ; eIF4E ; Eukaryotic Initiation Factor-4E - antagonists & inhibitors ; Eukaryotic Initiation Factor-4E - genetics ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Genetic translation ; Health aspects ; Humans ; Inhibitor drugs ; Multiple myeloma ; Multiple Myeloma - drug therapy ; Multiple Myeloma - genetics ; Multiple Myeloma - pathology ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Physiological aspects ; Protein biosynthesis ; Protein synthesis ; Proteins ; Proto-Oncogene Proteins c-myc - biosynthesis ; ribavirin ; Ribavirin - administration & dosage ; RNA, Small Interfering ; tetraspanins ; Tetraspanins - administration & dosage ; Tetraspanins - biosynthesis ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism ; Unfolded Protein Response - genetics ; velcade</subject><ispartof>International journal of oncology, 2015-02, Vol.46 (2), p.860-870</ispartof><rights>Copyright © 2015, Spandidos Publications</rights><rights>COPYRIGHT 2015 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-d750d28dc791dbe9b5e47d420f2bd8d35943d0145975223f5e05ae185534f40c3</citedby><cites>FETCH-LOGICAL-c490t-d750d28dc791dbe9b5e47d420f2bd8d35943d0145975223f5e05ae185534f40c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,5556,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25422161$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZISMANOV, VICTORIA</creatorcontrib><creatorcontrib>ATTAR-SCHNEIDER, OSHRAT</creatorcontrib><creatorcontrib>LISHNER, MICHAEL</creatorcontrib><creatorcontrib>AIZENFELD, RACHEL HEFFEZ</creatorcontrib><creatorcontrib>MATALON, SHELLY TARTAKOVER</creatorcontrib><creatorcontrib>DRUCKER, LIAT</creatorcontrib><title>Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin-induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c-Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti-viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti-MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.</description><subject>Akt</subject><subject>Antibiotics</subject><subject>Antiviral agents</subject><subject>Antiviral drugs</subject><subject>Autophagy - drug effects</subject><subject>Bone marrow</subject><subject>CD81N1</subject><subject>CD82N1</subject><subject>Cell Line, Tumor</subject><subject>Cyclin D1 - biosynthesis</subject><subject>Drug therapy</subject><subject>eIF4E</subject><subject>Eukaryotic Initiation Factor-4E - antagonists & inhibitors</subject><subject>Eukaryotic Initiation Factor-4E - genetics</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetic aspects</subject><subject>Genetic translation</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - pathology</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein biosynthesis</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-myc - biosynthesis</subject><subject>ribavirin</subject><subject>Ribavirin - administration & dosage</subject><subject>RNA, Small Interfering</subject><subject>tetraspanins</subject><subject>Tetraspanins - administration & dosage</subject><subject>Tetraspanins - biosynthesis</subject><subject>TOR Serine-Threonine Kinases - genetics</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Unfolded Protein Response - genetics</subject><subject>velcade</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkctLJDEQxsOirM_jXpeA4J4y5jndOYroKih7Wc8hnVRrhu7ObJIW_O_NMOoqSB2qCL96fPkQ-sHoQrSan4VVXHDK5II3jfyG9lmjGeGSi51aU6bJUgq9hw5yXlHKlaLsO9rjSnLOlmwf3d_NQwnrAfD4DEMcLV6nWCDmYnPI2NkJd4CLTQ9QwOOnYHFJdsqDLSFOOEyhhG3ZW1diwnBzJS-P0G5vhwzHr_kQ3V9d_r24Jrd_ft9cnN8SJzUtxDeKet56V2_2HehOgWy85LTnnW-9UFoKX7Up3SjORa-AKgusVUrIXlInDtHJdm49-t8MuZhVnNNUVxqmBW-FEIr-px7sACZMfawS3BiyM-eSMtEyqVmlFl9QNTyMwcUJ-lDfPzWcfmh4BDuUxxyHefMb-TNItqBLMecEvVmnMNr0bBg1GxNNNdFsTDQbEyv_81XV3I3g3-k31yrwawvktZ188DG_M3USkUtCOaHtkooXf7ehjw</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>ZISMANOV, VICTORIA</creator><creator>ATTAR-SCHNEIDER, OSHRAT</creator><creator>LISHNER, MICHAEL</creator><creator>AIZENFELD, RACHEL HEFFEZ</creator><creator>MATALON, SHELLY TARTAKOVER</creator><creator>DRUCKER, LIAT</creator><general>D.A. Spandidos</general><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20150201</creationdate><title>Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E</title><author>ZISMANOV, VICTORIA ; ATTAR-SCHNEIDER, OSHRAT ; LISHNER, MICHAEL ; AIZENFELD, RACHEL HEFFEZ ; MATALON, SHELLY TARTAKOVER ; DRUCKER, LIAT</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-d750d28dc791dbe9b5e47d420f2bd8d35943d0145975223f5e05ae185534f40c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Akt</topic><topic>Antibiotics</topic><topic>Antiviral agents</topic><topic>Antiviral drugs</topic><topic>Autophagy - drug effects</topic><topic>Bone marrow</topic><topic>CD81N1</topic><topic>CD82N1</topic><topic>Cell Line, Tumor</topic><topic>Cyclin D1 - biosynthesis</topic><topic>Drug therapy</topic><topic>eIF4E</topic><topic>Eukaryotic Initiation Factor-4E - antagonists & inhibitors</topic><topic>Eukaryotic Initiation Factor-4E - genetics</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genetic aspects</topic><topic>Genetic translation</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - genetics</topic><topic>Multiple Myeloma - pathology</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein biosynthesis</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-myc - biosynthesis</topic><topic>ribavirin</topic><topic>Ribavirin - administration & dosage</topic><topic>RNA, Small Interfering</topic><topic>tetraspanins</topic><topic>Tetraspanins - administration & dosage</topic><topic>Tetraspanins - biosynthesis</topic><topic>TOR Serine-Threonine Kinases - genetics</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Unfolded Protein Response - genetics</topic><topic>velcade</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ZISMANOV, VICTORIA</creatorcontrib><creatorcontrib>ATTAR-SCHNEIDER, OSHRAT</creatorcontrib><creatorcontrib>LISHNER, MICHAEL</creatorcontrib><creatorcontrib>AIZENFELD, RACHEL HEFFEZ</creatorcontrib><creatorcontrib>MATALON, SHELLY TARTAKOVER</creatorcontrib><creatorcontrib>DRUCKER, LIAT</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Nursing & Allied Health Premium</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><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ZISMANOV, VICTORIA</au><au>ATTAR-SCHNEIDER, OSHRAT</au><au>LISHNER, MICHAEL</au><au>AIZENFELD, RACHEL HEFFEZ</au><au>MATALON, SHELLY TARTAKOVER</au><au>DRUCKER, LIAT</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>46</volume><issue>2</issue><spage>860</spage><epage>870</epage><pages>860-870</pages><issn>1019-6439</issn><eissn>1791-2423</eissn><abstract>Intensive protein synthesis is a unique and differential trait of the multiple myeloma (MM) cells. Previously we showed that tetraspanin overexpression in MM cell lines attenuated mTOR and PI3K cascades, induced protein synthesis, activated unfolded protein response (UPR), and caused autophagic death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin-induced MM cell death with emphasis on eIF4E translation initiation factor. We showed tetraspanins attenuated peIF4E and its targets [c-Myc, cyclin D1 (cycD1)]; eIF4E attenuation was Akt-dependent. eIF4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti-viral drug and competitive eIF4E inhibitor ribavirin (RBV) deleteriously affected MM cells in a similar manner to the overexpression of tetraspanins. Furthermore, combined application of RBV and velcade had a synergistic anti-MM effect. Our results demonstrate that breach of proteostasis via eIF4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.</abstract><cop>Greece</cop><pub>D.A. Spandidos</pub><pmid>25422161</pmid><doi>10.3892/ijo.2014.2774</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1019-6439 |
| ispartof | International journal of oncology, 2015-02, Vol.46 (2), p.860-870 |
| issn | 1019-6439 1791-2423 |
| language | eng |
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| source | Spandidos Publications Journals; MEDLINE; Alma/SFX Local Collection; EZB Electronic Journals Library |
| subjects | Akt Antibiotics Antiviral agents Antiviral drugs Autophagy - drug effects Bone marrow CD81N1 CD82N1 Cell Line, Tumor Cyclin D1 - biosynthesis Drug therapy eIF4E Eukaryotic Initiation Factor-4E - antagonists & inhibitors Eukaryotic Initiation Factor-4E - genetics Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Genetic translation Health aspects Humans Inhibitor drugs Multiple myeloma Multiple Myeloma - drug therapy Multiple Myeloma - genetics Multiple Myeloma - pathology Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Physiological aspects Protein biosynthesis Protein synthesis Proteins Proto-Oncogene Proteins c-myc - biosynthesis ribavirin Ribavirin - administration & dosage RNA, Small Interfering tetraspanins Tetraspanins - administration & dosage Tetraspanins - biosynthesis TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Unfolded Protein Response - genetics velcade |
| title | Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E |
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