Priority Research Papers:
Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
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Mary Pulvino1, Luojing Chen2, David Oleksyn2, Jing Li3, George Compitello1, Randy Rossi4, Stephen Spence5, Vijaya Balakrishnan1, Craig Jordan4,6, Brian Poligone7, Carla Casulo4, Richard Burack5, Joel L. Shapiro8, Steven Bernstein4, Jonathan W. Friedberg4, Raymond J. Deshaies3,9, Hartmut Land1,4, Jiyong Zhao1,4
1Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
2Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA
3Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
4Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
5Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA
6Division of Hematology, University of Colorado Denver, Aurora, CO, USA
7Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA
8Department of Pathology, Rochester General Hospital, Rochester, NY, USA
9Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA
Jiyong Zhao, e-mail: [email protected]
Keywords: DLBCL, doxycycline, therapeutic agent, COP-9 signalosome, CSN5
Received: April 06, 2015 Accepted: May 22, 2015 Published: June 04, 2015
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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