Abstract
Non-Hodgkin lymphomas (NHLs) are characterized by specific abnormalities that alter cell cycle regulation, DNA damage response, and apoptotic signaling. It is believed that cancer cells are particularly sensitive to cell death induced by tumor necrosis factor α–related apoptosis-inducing ligand (TRAIL). However, many cancer cells show blocked TRAIL signaling due to up-regulated expression of anti-apoptotic factors, such as cFLIP. This hurdle to TRAIL’s tumor cytotoxicity might be overcome by combining TRAIL-based therapy with drugs that reverse blockages of its apoptotic signaling. In this study, we investigated the impact of a pan-methyltransferase inhibitor (3-deazaneplanocin A, or DZNep) on TRAIL-induced apoptosis in aggressive B-cell NHLs: mantle cell, Burkitt, and diffuse large B-cell lymphomas. We characterized TRAIL apoptosis regulation and caspase activation in several NHL-derived cell lines pre-treated with DZNep. We found that DZNep increased cancer cell sensitivity to TRAIL signaling by promoting caspase-8 processing through accelerated cFLIP degradation. No change in cFLIP mRNA level indicated independence of promoter methylation alterations in methyltransferase activity induced by DZNep profoundly affected cFLIP mRNA stability and protein stability. This appears to be in part through increased levels of cFLIP-targeting microRNAs (miR-512-3p and miR-346). However, additional microRNAs and cFLIP-regulating mechanisms appear to be involved in DZNep-mediated enhanced response to extrinsic apoptotic stimuli. The capacity of DZNep to target cFLIP expression on multiple levels underscores DZNep’s potential in TRAIL-based therapies for B-cell NHLs.
Highlights
Non-Hodgkin lymphomas (NHLs), a highly heterogeneous group of lymphoproliferative neoplasms, were the eighth most prevalent cancer in the United States and the sixth most prevalent cancer in U.S males in 2010
To test whether DZNep affects tumor necrosis factor α–related apoptosis-inducing ligand (TRAIL) signaling in various NHL B-cell lymphoma-derived cell lines, we investigated apoptosis induced by treatment with TRAIL in cells pre-treated with DZNep
Our results indicate that inhibition of methyltransferase activity leads to destabilization of cFLIP mRNA and enhanced degradation of cFLIP protein in NHL-derived cell lines
Summary
Non-Hodgkin lymphomas (NHLs), a highly heterogeneous group of lymphoproliferative neoplasms, were the eighth most prevalent cancer in the United States and the sixth most prevalent cancer in U.S males in 2010. DZNep Increases Sensitivity to Apoptosis by cFLIP Degradation of afflicted individuals are diffuse large B-cell lymphoma, mantle cell lymphoma, and Burkitt lymphoma, which account for 30%-40%, 5%, and 1%-2% of NHLs, respectively [17, 20, 29, 43]. The survival of individuals with NHL has improved with the addition of targeted therapies to conventional chemotherapy regimens. Despite the use of targeted therapy and chemotherapy, NHLs show frequent relapses [38, 53]. Even the recently approved drugs for relapsed NHL, temsirolimus, bortezomib and ibrutinib, show only incremental improvement and patients still face an expected 5 year survival slightly above 50%. Additional new targets and approaches to improve the efficacy of NHL therapy are urgently needed [57]
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