Demethylating agent 5-aza-2'-deoxycytidine enhances expression of TNFRI and promotes TNF-mediated apoptosis in vitro and in vivo.
Promoter hypermethylation within CpG islands plays an important role in the silencing of numerous genes involved in tumor growth including tumor suppressor genes and genes encoding proteins involved in the execution of apoptosis. Here we show that CpG islands are also found within the promoter regions of both human and mouse TNFR1 (TNFRSF1) genes. Selective inhibition of methyltransferases with 5-aza-2'-deoxycytidine increases the expression of TNFR1 in human (WM35) and murine (B16F10) melanoma cells and sensitizes them to TNF-induced apoptosis both in vitro and in vivo. Treatment of mice with the combination of 5-aza-2'-deoxycytidine and recombinant TNF leads to potentiated antitumor effects. Importantly the antitumor efficacy of the combination treatment is shown when both drugs are used in doses that do not exert any antitumor effects when used alone. Altogether our studies show that the combination treatment with 5-aza-2'-deoxycytidine and TNF might be effective in the treatment of melanoma.
Kaminski
Rafal
R
Department of Immunology, Center of Biostructure, The Medical University of Warsaw, ul. Chalubinskiego 5, 02-004 Warsaw, Poland.
Kozar
Katarzyna
K
Niderla
Justyna
J
Grzela
Tomasz
T
Wilczynski
Grzegorz
G
Skierski
Janusz S
JS
Koronkiewicz
Miroslawa
M
Jakobisiak
Marek
M
Golab
Jakub
J
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D018899:CpG Islands; D053938:DNA Fragmentation; D000077209:Decitabine; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009336:Necrosis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000737:chemistry; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D000077209:Decitabine; D012260:Ribonucleases; D001374:Azacitidine