title: Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells.
abstract: miRs play a critical role in tumor pathogenesis as either oncogenes or tumor-suppressor genes. However, the role of miRs and their regulation in response to proteasome inhibitors in multiple myeloma (MM) is unclear. In the current study, miR profiling in proteasome inhibitor MLN2238-treated MM.1S MM cells shows up-regulation of miR33b. Mechanistic studies indicate that the induction of miR33b is predominantly via transcriptional regulation. Examination of miR33b in patient MM cells showed a constitutively low expression. Overexpression of miR33b decreased MM cell viability, migration, colony formation, and increased apoptosis and sensitivity of MM cells to MLN2238 treatment. In addition, overexpression of miR33b or MLN2238 exposure negatively regulated oncogene PIM-1 and blocked PIM-1 wild-type, but not PIM-1 mutant, luciferase activity. Moreover, PIM-1 overexpression led to significant abrogation of miR33b- or MLN2238-induced cell death. SGI-1776, a biochemical inhibitor of PIM-1, triggered apoptosis in MM. Finally, overexpression of miR33b inhibited tumor growth and prolonged survival in both subcutaneous and disseminated human MM xenograft models. Our results show that miR33b is a tumor suppressor that plays a role during MLN2238-induced apoptotic signaling in MM cells, and these data provide the basis for novel therapeutic strategies targeting miR33b in MM.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ze
authors.initials: Z
authors.lastname: Tian
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Samir B
authors.initials: SB
authors.lastname: Amin
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Hu
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001896:Boron Compounds; D007093:Imidazoles; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D011724:Pyridazines; C545188:SGI 1776; C548400:ixazomib; D051573:Proto-Oncogene Proteins c-pim-1; D005998:Glycine