title: MiRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc.
abstract: The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc. The baseline expression of miR-29a was significantly lower in MM cell lines and MM patient samples compared to normal hematopoietic cells. In addition, ectopic expression of miRNA-29a or exposure to PRIMA-1Met reduced cell proliferation and induced apoptosis in MM cells. On the other hand, overexpression of c-Myc at least partially reverted the inhibitory effects of PRIMA-1Met or miRNA-29a overexpression suggesting the miRNA-29a/c-Myc axis mediates anti-myeloma effects of PRIMA-1Met. Importantly, intratumor delivery of miRNA-29a mimics induced regression of tumors in mouse xenograft model of MM and this effect synergized with PRIMA-1Met. Our study indicates that miRNA-29a is a tumor suppressor that plays an important role during PRIMA-1Met-induced apoptotic signaling by targeting c-Myc and provides the basis for novel therapeutic strategies using miRNA-29a mimics combined with PRIMA-1Met in MM.
authors.affiliation: Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Current address: Department of Surgery, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Manujendra N
authors.initials: MN
authors.lastname: Saha
authors.affiliation: Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Abdi
authors.affiliation: Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Department of Applied Chemistry, School of Chemical Engineering and Technology, Tianjin University, Tianjin, P. R. China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Department of Laboratory Hematology and Medical Oncology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; C532045:MIRN29a microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D011812:Quinuclidines; D012333:RNA, Messenger; C533410:eprenetapopt
keywords: Myc; apoptosis; miRNA-29a; myeloma