Inhibition of Methyltransferases Accelerates Degradation of cFLIP and Sensitizes B-Cell Lymphoma Cells to TRAIL-Induced Apoptosis

被引:17
作者
Braun, Frank K. [1 ]
Mathur, Rohit [1 ]
Sehgal, Lalit [1 ]
Wilkie-Grantham, Rachel [3 ]
Chandra, Joya [2 ]
Berkova, Zuzana [1 ]
Samaniego, Felipe [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA
[3] Sanford Burnham Med Res Inst, La Jolla, CA USA
关键词
C-FLIP; DEATH RECEPTORS; KAPPA-B; CANCER; METHYLATION; TARGETS; EZH2; REGULATORS; RITUXIMAB; MICRORNAS;
D O I
10.1371/journal.pone.0117994
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 alpha-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.
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页数:17
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