title: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.
abstract: Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation owing to diminished mTORC1 (mammalian target of rapamycin complex1) activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES (internal ribosome entry site) function, which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent on upstream MAPK (mitogen-activated protein kinase) and MNK1 (MAPK-interacting serine/threonine kinase 1) signaling. A screen identified hnRNP A1 (A1) and RPS25 as IRES-binding trans-acting factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by an MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress.
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Hoang
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bardeleben
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Holmes
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gera
authors.affiliation: Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lichtenstein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D002460:Cell Line; D016503:Drug Delivery Systems; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D016259:Genes, myc; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000187:drug effects / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D009101:Multiple Myeloma / Q000235:genetics*; D046912:Multiprotein Complexes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000067556:Internal Ribosome Entry Sites; D046912:Multiprotein Complexes; D014415:Tunicamycin; D019284:Thapsigargin; D000069286:Bortezomib; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases