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.
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.Attached Files
Published - 4193-59467-3-PB.pdf
Supplemental Material - 4193-59477-1-SP.pdf
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Additional details
- PMCID
- PMC4558116
- Eprint ID
- 58776
- Resolver ID
- CaltechAUTHORS:20150706-111955387
- University of Rochester Wilmor Cancer Institute
- Two Sisters and a Wife Foundation
- R01 CA127530
- NIH
- R01 GM065997
- NIH
- R01 CA164803
- NIH
- Howard Hughes Medical Institute (HHMI)
- Created
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2015-07-06Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field