The role of IFN regulatory factor-3 in the cytotoxic activity of NS-9, a polyinosinic-polycytidylic acid/cationic liposome complex, against tumor cells.
NS-9 is a complex of polyinosinic-polycytidylic acid and a novel cationic liposome, LIC-101. The complex has strong cytotoxic activity against tumor cells derived from epithelial or fibroblastic cells. We have investigated the mechanism of the cytotoxic activity of NS-9 using knockdown cells in which the expression of proteins of interest was inhibited by RNA interference. NS-9 showed strong cytotoxic activity against knockdown cells with reduced expression of double-stranded RNA-dependent protein kinase, RNase L, or IFN-alpha/beta receptor, but showed no cytotoxic activity against IFN regulatory factor-3 (IRF3) knockdown cells. In IRF3-knockdown cells, NS-9 also did not induce either the DNA fragmentation or the rRNA degradation observed in negative control cells. We conclude that IRF3 plays a crucial role in the cytotoxic activity of NS-9 against tumor cells, whereas RNA-dependent protein kinase, RNase L, or type I IFNs are not important for its activity.
Uno
Tomonori
T
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchi-cho, Kisshoin, Minami, Kyoto 601-8550, Japan. t.uno@po.nippon-shinyaku.co.jp
Hirabayashi
Kazuko
K
Murai
Masatoshi
M
Yano
Junichi
J
Ozato
Keiko
K
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis; D002412:Cations; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008081:Liposomes; D011070:Poly I-C / Q000494:pharmacology*; D034622:RNA Interference; D012335:RNA, Ribosomal / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002412:Cations; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D008081:Liposomes; D012335:RNA, Ribosomal; D014157:Transcription Factors; D016899:Interferon-beta; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D011070:Poly I-C