title: A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance.
abstract: Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma cells, and overcomes bortezomib resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM.
authors: Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and.
authors: Ze
authors: Z
authors: Tian
authors: Padraig
authors: P
authors: D'Arcy
authors: Xin
authors: X
authors: Wang
authors: Arghya
authors: A
authors: Ray
authors: Yu-Tzu
authors: YT
authors: Tai
authors: Yiguo
authors: Y
authors: Hu
authors: Ruben D
authors: RD
authors: Carrasco
authors: Paul
authors: P
authors: Richardson
authors: Stig
authors: S
authors: Linder
authors: Dharminder
authors: D
authors: Chauhan
authors: Kenneth C
authors: KC
authors: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010881:Piperidones / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015854:Up-Regulation
chemical_list: C569633:3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one; D000970:Antineoplastic Agents; D001897:Boronic Acids; D010881:Piperidones; D011480:Protease Inhibitors; D011719:Pyrazines; C509299:USP14 protein, human; D000069286:Bortezomib; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase