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 death, all suggesting breach of proteostasis. Here we assessed the role of translation initiation in the tetraspanin-induced MM cell death with emphasis on eIF 4E translation initiation factor. We showed tetraspanins attenuated peIF 4E and its targets [c-Myc, cyclin D1 (cycD1)]; eIF 4E attenuation was Akt-dependent. eIF 4E inhibition in MM cells [bone marrow (BM), lines] by siRNA and/or the anti-viral drug and competitive eIF 4E 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 eIF 4E inhibition is an attractive therapeutic approach that may be relatively easily achieved by employing RBV, making this strategy readily translatable into the clinic.