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

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 ca...

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Autores principales: Pulvino, Mary, Chen, Luojing, Oleksyn, David, Li, Jing, Compitello, George, Rossi, Randy, Spence, Stephen, Balakrishnan, Vijaya, Jordan, Craig, Poligone, Brian, Casulo, Carla, Burack, Richard, Shapiro, Joel L., Bernstein, Steven, Friedberg, Jonathan W., Deshaies, Raymond J., Land, Hartmut, Zhao, Jiyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558116/
https://www.ncbi.nlm.nih.gov/pubmed/26142707
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author Pulvino, Mary
Chen, Luojing
Oleksyn, David
Li, Jing
Compitello, George
Rossi, Randy
Spence, Stephen
Balakrishnan, Vijaya
Jordan, Craig
Poligone, Brian
Casulo, Carla
Burack, Richard
Shapiro, Joel L.
Bernstein, Steven
Friedberg, Jonathan W.
Deshaies, Raymond J.
Land, Hartmut
Zhao, Jiyong
author_facet Pulvino, Mary
Chen, Luojing
Oleksyn, David
Li, Jing
Compitello, George
Rossi, Randy
Spence, Stephen
Balakrishnan, Vijaya
Jordan, Craig
Poligone, Brian
Casulo, Carla
Burack, Richard
Shapiro, Joel L.
Bernstein, Steven
Friedberg, Jonathan W.
Deshaies, Raymond J.
Land, Hartmut
Zhao, Jiyong
author_sort Pulvino, Mary
collection PubMed
description 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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spelling pubmed-45581162015-09-09 Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline Pulvino, Mary Chen, Luojing Oleksyn, David Li, Jing Compitello, George Rossi, Randy Spence, Stephen Balakrishnan, Vijaya Jordan, Craig Poligone, Brian Casulo, Carla Burack, Richard Shapiro, Joel L. Bernstein, Steven Friedberg, Jonathan W. Deshaies, Raymond J. Land, Hartmut Zhao, Jiyong Oncotarget Priority Research Paper 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. Impact Journals LLC 2015-06-04 /pmc/articles/PMC4558116/ /pubmed/26142707 Text en Copyright: © 2015 Pulvino et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Pulvino, Mary
Chen, Luojing
Oleksyn, David
Li, Jing
Compitello, George
Rossi, Randy
Spence, Stephen
Balakrishnan, Vijaya
Jordan, Craig
Poligone, Brian
Casulo, Carla
Burack, Richard
Shapiro, Joel L.
Bernstein, Steven
Friedberg, Jonathan W.
Deshaies, Raymond J.
Land, Hartmut
Zhao, Jiyong
Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title_full Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title_fullStr Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title_full_unstemmed Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title_short Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline
title_sort inhibition of cop9-signalosome (csn) deneddylating activity and tumor growth of diffuse large b-cell lymphomas by doxycycline
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558116/
https://www.ncbi.nlm.nih.gov/pubmed/26142707
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