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: 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, Jiyong Zhao
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 14796-813 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26142707 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• HSP90 Heat-Shock Proteins
• Il2rg protein, mouse
• Interleukin Receptor Common gamma Subunit
• Intracellular Signaling Peptides and Proteins
• Multiprotein Complexes
• Peptide Hydrolases
• COPS5 protein, human
• COP9 Signalosome Complex
• Doxycycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Blotting, Western
• COP9 Signalosome Complex
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Doxycycline (pharmacology)
• Female
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Interleukin Receptor Common gamma Subunit (deficiency, genetics)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, metabolism)
• Lymphoma, Non-Hodgkin (genetics, metabolism)
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Multiprotein Complexes (genetics, metabolism)
• Peptide Hydrolases (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays