title: Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline.
abstract: In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Pulvino
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Luojing
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oleksyn
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: George
authors.initials: G
authors.lastname: Compitello
authors.affiliation: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Randy
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Spence
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Balakrishnan
authors.affiliation: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.|Division of Hematology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Jordan
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Poligone
authors.affiliation: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Casulo
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Burack
authors.affiliation: Department of Pathology, Rochester General Hospital, Rochester, NY, USA.
authors.forename: Joel L
authors.initials: JL
authors.lastname: Shapiro
authors.affiliation: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Bernstein
authors.affiliation: Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.|Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.|Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Land
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.|Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D000075686:COP9 Signalosome Complex; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000900:Anti-Bacterial Agents; D018841:HSP90 Heat-Shock Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D004318:Doxycycline
keywords: COP-9 signalosome; CSN5; DLBCL; doxycycline; therapeutic agent