Inhibition of methyltransferases accelerates degradation of cFLIP and sensitizes B-cell lymphoma cells to TRAIL-induced apoptosis

PloS One
Frank K BraunFelipe Samaniego

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 mR...Continue Reading

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Citations

Nov 19, 2015·International Journal of Molecular Sciences·Mónica Martínez-FernándezJesús M Paramio
Oct 21, 2015·Oncotarget·Katarzyna KlonowskaPiotr Kozlowski
Dec 31, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Adel NaimiSaeed Solali

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Datasets Mentioned

BETA
GSE10846

Methods Mentioned

BETA
flow cytometry
transfection
ubiquitination
Assay
PCR

Software Mentioned

Image J
StepOne
ImageJ
FlowJo

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