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

2015; Impact Journals LLC; Volume: 6; Issue: 17 Linguagem: Inglês

10.18632/oncotarget.4193

1949-2553

Mary J. Pulvino, Luojing Chen, David Oleksyn, Jing Li, George Compitello, Randy Rossi, Stephen A. Spence, Vijaya Balakrishnan, Craig T. Jordan, Brian Poligone, Carla Casulo, Richard Burack, Joël Shapiro, Steven H. Bernstein, Jonathan W. Friedberg, Raymond J. Deshaies, Hartmut Land, Jiyong Zhao,

Histone Deacetylase Inhibitors Research

// Mary Pulvino 1 , Luojing Chen 2 , David Oleksyn 2 , Jing Li 3 , George Compitello 1 , Randy Rossi 4 , Stephen Spence 5 , Vijaya Balakrishnan 1 , Craig Jordan 4, 6 , Brian Poligone 7 , Carla Casulo 4 , Richard Burack 5 , Joel L. Shapiro 8 , Steven Bernstein 4 , Jonathan W. Friedberg 4 , Raymond J. Deshaies 3, 9 , Hartmut Land 1, 4 , Jiyong Zhao 1, 4 1 Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA 2 Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA 3 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA 4 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA 5 Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA 6 Division of Hematology, University of Colorado Denver, Aurora, CO, USA 7 Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA 8 Department of Pathology, Rochester General Hospital, Rochester, NY, USA 9 Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA Correspondence to: Jiyong Zhao, e-mail: Jiyong_zhao@urmc.rochester.edu Keywords: DLBCL, doxycycline, therapeutic agent, COP-9 signalosome, CSN5 Received: April 06, 2015 Accepted: May 22, 2015 Published: June 04, 2015 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.