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Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

Pulvino, Mary and Chen, Luojing and Oleksyn, David and Li, Jing and Compitello, George and Rossi, Randy and Spence, Stephen and Balakrishnan, Vijaya and Jordan, Craig and Poligone, Brian and Casulo, Carla and Burack, Richard and Shapiro, Joel L. and Bernstein, Steven and Friedberg, Jonathan W. and Deshaies, Raymond J. and Land, Hartmut and Zhao, Jiyong (2015) Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline. Oncotarget, 6 (17). pp. 14796-14813. ISSN 1949-2553. PMCID PMC4558116.

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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.

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Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2015 Impact Journals, LLC. Creative Commons Attribution 3.0 License. Received: April 06, 2015 Accepted: May 22, 2015 Published: June 04, 2015. We thank Dr. Dirk Bohmann for discussions and critical reading of the manuscript; Dr. Sylvie Urbe for the pGEX-AMSH plasmid; Dr. John Ashton for the OCI-Ly10 cell line with an integrated NF-κB-Luciferase reporter; University of Rochester Proteomic Center for analysis of doxycycline concentrations by mass spectrometry. This work was supported by a seed grant from Wilmot Cancer Institute of University of Rochester and a grant from Two Sisters and a Wife Foundation. Work on NF-κB signaling in DLBCL in Zhao laboratory was supported by NIH R01 CA127530. Work on the CSN5 and RPN11 assays in the Deshaies laboratory was supported by NIH R01 GM065997, R01 CA164803, and the Howard Hughes Medical Institute. RJD is an Investigator of the HHMI.
Funding AgencyGrant Number
University of Rochester Wilmor Cancer InstituteUNSPECIFIED
Two Sisters and a Wife FoundationUNSPECIFIED
NIHR01 CA127530
NIHR01 GM065997
NIHR01 CA164803
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:DLBCL, doxycycline, therapeutic agent, COP-9 signalosome, CSN5
Issue or Number:17
PubMed Central ID:PMC4558116
Record Number:CaltechAUTHORS:20150706-111955387
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Official Citation:Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline Mary Pulvino, Luojing Chen, David Oleksyn, Jing Li, George Compitello, Randy Rossi, Stephen Spence, Vijaya Balakrishnan, Craig Jordan, Brian Poligone, Carla Casulo, Richard Burack, Joel L. Shapiro, Steven Bernstein, Jonathan W. Friedberg, Raymond J. Deshaies, Hartmut Land, and Jiyong Zhao 14796-14813
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58776
Deposited By: Ruth Sustaita
Deposited On:06 Jul 2015 20:12
Last Modified:03 Mar 2020 00:16

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