title: Polymethoxylated flavones potentiate the cytolytic activity of NK leukemia cell line KHYG-1 via enhanced expression of granzyme B.
abstract: Polymethoxylated flavones (PMFs) are found in the peel tissues of some citrus species. Here, we report that PMFs, such as nobiletin, potentiate the cytolytic activity of KHYG-1 natural killer (NK) leukemia cells. Nobiletin markedly enhanced the expression of granzyme B, a serine protease that plays critical roles in the cytolytic activity of NK cells. The potentiated cytolytic activity induced by nobiletin was canceled by the granzyme B inhibitor Z-AAD-CMK. Nobiletin also increased the levels of phosphorylated CREB, ERK1/2, and p38 MAPK in KHYG-1 cells, which are known to participate in NK cell function. Inhibition of an upstream kinase of ERK1/2 failed to reduce the granzyme B expression and KHYG-1 cytolytic activity. Meanwhile, inhibition of p38 MAPK attenuated both granzyme B expression and KHYG-1 cytolytic activity. These results suggest that the primary role of nobiletin in KHYG-1 cytolytic activity lies in upregulation of granzyme B expression, at least in part, mediated through p38 MAPK function.
authors.affiliation: NARO Western Region Agricultural Research Center, Kagawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Saito
authors.affiliation: NARO Western Region Agricultural Research Center, Kagawa, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Abe
authors.affiliation: NARO Western Region Agricultural Research Center, Kagawa, Japan. Electronic address: ynogata@affrc.go.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nogata
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002957:Citrus / Q000737:chemistry; D047309:Flavones / Q000302:isolation & purification / Q000494:pharmacology*; D053804:Granzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D047309:Flavones; C440223:Z-Ala-Ala-Asp-chloromethylketone; C008661:nobiletin; D048051:p38 Mitogen-Activated Protein Kinases; D053804:Granzymes
keywords: Granzyme B; KHYG-1; NK cell; Nobiletin; Polymethoxylated flavone; p38 MAPK