Inhibition of methyltransferases accelerates degradation of cFLIP and sensitizes B-cell lymphoma cells to TRAIL-induced apoptosis.
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.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Frank K
FK
Braun
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Rohit
R
Mathur
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Lalit
L
Sehgal
Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
Rachel
R
Wilkie-Grantham
Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Joya
J
Chandra
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Zuzana
Z
Berkova
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Felipe
F
Samaniego
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059748:Proteolysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C048460:3-deazaneplanocin; D008780:Methyltransferases; D000241:Adenosine