Oncotarget

Priority Research Papers:

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

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Oncotarget. 2015; 6:14796-14813. https://doi.org/10.18632/oncotarget.4193

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Abstract

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

Correspondence to:

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

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.


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