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

Pulvino M, Chen L, Oleksyn D, Li J, Compitello G, Rossi R, Spence S, Balakrishnan V, Jordan C, Poligone B, Casulo C, Burack R, Shapiro JL, Bernstein S, Friedberg JW, Deshaies RJ, Land H, Zhao J - Oncotarget (2015)

Bottom Line: 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.Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus

CSN5 is required for the survival in DLBCL cellsA. DLBCL cells were infected with lentiviruses that express shControl, shCSN5-A or shCSN5-B. Seventy-two (for OCI-Ly7) or 96 hours (for OCI-Ly10) after infection, the viability of the infected cells, which express GFP from the viral vector, were analyzed by flow cytometry. Shown are mean and SD from a representative experiment with triplicate samples. B. DLBCL cells were infected with the indicated shRNA-expressing lentiviruses. The levels of the indicated proteins in the infected cells were analyzed by western blotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4558116&req=5

Figure 7: CSN5 is required for the survival in DLBCL cellsA. DLBCL cells were infected with lentiviruses that express shControl, shCSN5-A or shCSN5-B. Seventy-two (for OCI-Ly7) or 96 hours (for OCI-Ly10) after infection, the viability of the infected cells, which express GFP from the viral vector, were analyzed by flow cytometry. Shown are mean and SD from a representative experiment with triplicate samples. B. DLBCL cells were infected with the indicated shRNA-expressing lentiviruses. The levels of the indicated proteins in the infected cells were analyzed by western blotting.

Mentions: The observations presented above suggest that doxycycline may exert its growth inhibitory effect on DLBCL cells through inhibition of CSN5. This view predicts that CSN5 is required for the survival of DLBCL cells. To test this predication, we examined the effects of CSN5 knockdown in DLBCL cells. Depletion of CSN5 led to marked increases in DLBCL cell death (Figure 7A), demonstrating that CSN5 is an essential survival factor for DLBCL cells. As observed with doxycycline treatment, CSN5 knockdown resulted in reduction in the levels of several HSP90 client proteins as well as HSP70 and HSP90 proteins in both DLBCL cells (Figure 7B) and non-lymphoma cells (Supplementary Figure 7). Thus, CSN5 depletion exhibits the biological and biochemical effects shown for doxycycline treatment in DLBCL cells, consistent with the suggestion that CSN5 is a critical target of the antineoplastic action of doxycycline in DLBCL cells.


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

Pulvino M, Chen L, Oleksyn D, Li J, Compitello G, Rossi R, Spence S, Balakrishnan V, Jordan C, Poligone B, Casulo C, Burack R, Shapiro JL, Bernstein S, Friedberg JW, Deshaies RJ, Land H, Zhao J - Oncotarget (2015)

CSN5 is required for the survival in DLBCL cellsA. DLBCL cells were infected with lentiviruses that express shControl, shCSN5-A or shCSN5-B. Seventy-two (for OCI-Ly7) or 96 hours (for OCI-Ly10) after infection, the viability of the infected cells, which express GFP from the viral vector, were analyzed by flow cytometry. Shown are mean and SD from a representative experiment with triplicate samples. B. DLBCL cells were infected with the indicated shRNA-expressing lentiviruses. The levels of the indicated proteins in the infected cells were analyzed by western blotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4558116&req=5

Figure 7: CSN5 is required for the survival in DLBCL cellsA. DLBCL cells were infected with lentiviruses that express shControl, shCSN5-A or shCSN5-B. Seventy-two (for OCI-Ly7) or 96 hours (for OCI-Ly10) after infection, the viability of the infected cells, which express GFP from the viral vector, were analyzed by flow cytometry. Shown are mean and SD from a representative experiment with triplicate samples. B. DLBCL cells were infected with the indicated shRNA-expressing lentiviruses. The levels of the indicated proteins in the infected cells were analyzed by western blotting.
Mentions: The observations presented above suggest that doxycycline may exert its growth inhibitory effect on DLBCL cells through inhibition of CSN5. This view predicts that CSN5 is required for the survival of DLBCL cells. To test this predication, we examined the effects of CSN5 knockdown in DLBCL cells. Depletion of CSN5 led to marked increases in DLBCL cell death (Figure 7A), demonstrating that CSN5 is an essential survival factor for DLBCL cells. As observed with doxycycline treatment, CSN5 knockdown resulted in reduction in the levels of several HSP90 client proteins as well as HSP70 and HSP90 proteins in both DLBCL cells (Figure 7B) and non-lymphoma cells (Supplementary Figure 7). Thus, CSN5 depletion exhibits the biological and biochemical effects shown for doxycycline treatment in DLBCL cells, consistent with the suggestion that CSN5 is a critical target of the antineoplastic action of doxycycline in DLBCL cells.

Bottom Line: 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.Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus