title: Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E.
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.
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zismanov
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Attar-Schneider
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Lishner
authors.affiliation: Geriatric Department, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Heffez Aizenfeld
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Tartakover Matalon
authors.affiliation: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D034741:RNA, Small Interfering; D012254:Ribavirin / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059470:Tetraspanins / Q000008:administration & dosage / Q000096:biosynthesis; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D019938:Cyclin D1; D039561:Eukaryotic Initiation Factor-4E; D019869:Phosphatidylinositol 3-Kinases; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D012254:Ribavirin; D058570:TOR Serine-Threonine Kinases; D059470:Tetraspanins; C485950:TSPAN32 protein, human; C546842:MTOR protein, human