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.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for about one third of all the cases
While short treatment with doxycycline had no inhibitory effect on NF-κB activation in OCI-Ly10 cells, an activated B-cell (ABC)-diffuse large B-cell lymphoma (DLBCL) cell line that displays constitutive NF-κB signaling [11, 13], incubation of these cells with doxycycline for 12 hours decreased mRNA levels of several NF-κB targets (Figure 1A), which had been shown previously to be regulated by NF-κ B in these cells [13, 14], or exhibited the greatest response to doxycycline treatment among the queried NF-κB targets in the cMAP database (MCL-1)
We show that doxycycline affects several oncogenic signaling pathways, including the NF-κB, signal transducer and transcription factor 3 (STAT3), ERK and AKT pathways, critical for lymphomagenesis in DLBCL cells
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for about one third of all the cases. Gene expression profiling studies have classified DLBCLs into at least three major subgroups: the germinal center B-cell (GCB), the www.impactjournals.com/oncotarget activated B-cell (ABC), and the mediastinal large B-cell (PMBL) DLBCL [5–7]. All ABC DLBCL, the least curable DLBCL subtype, and a significant fraction of GCB DLBCL exhibit constitutive NF-κB pathway activity [5, 8–12]. ABC DLBCL cells depend on constitutive NF-κB signaling for proliferation and survival [11, 13–15]. Targeting pathways required for NF-κB activation has been proposed as a novel treatment strategy for DLBCL [16, 17]
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