Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF transcription by targeting the phosphotidylinositol 3-kinase/Akt pathway.
Previous studies have shown that freeze-dried black raspberry extract fractions inhibit benzo(a)pyrene [B(a)P]-induced transformation of Syrian hamster embryo cells and benzo(a)pyrene diol-epoxide [B(a)PDE]-induced activator protein-1 (AP-1) activity in mouse epidermal Cl 41 cells. The phosphotidylinositol 3-kinase (PI-3K)/Akt pathway is critical for B(a)PDE-induced AP-1 activation in mouse epidermal Cl 41 cells. In the present study, we determined the potential involvement of PI-3K and its downstream kinases on the inhibition of AP-1 activation by black raspberry fractions, RO-FOO3, RO-FOO4, RO-ME, and RO-DM. In addition, we investigated the effects of these fractions on the expression of the AP-1 target genes, vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Pretreatment of Cl 41 cells with fractions RO-F003 and RO-ME reduced activation of AP-1 and the expression of VEGF, but not iNOS. In contrast, fractions RO-F004 and RO-DM had no effect on AP-1 activation or the expression of either VEGF or iNOS. Consistent with inhibition of AP-1 activation, the RO-ME fraction markedly inhibited activation of PI-3K, Akt, and p70 S6 kinase (p70(S6k)). In addition, overexpression of the dominant negative PI-3K mutant delta p85 reduced the induction of VEGF by B(a)PDE. It is likely that the inhibitory effects of fractions RO-FOO3 and RO-ME on B(a)PDE-induced AP-1 activation and VEGF expression are mediated by inhibition of the PI-3K/Akt pathway. In view of the important roles of AP-1 and VEGF in tumor development, one mechanism for the chemopreventive activity of black raspberries may be inhibition of the PI-3K/Akt/AP-1/VEGF pathway.
Huang
Chuanshu
C
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA. chuanshu@env.med.nyu.edu
Li
Jingxia
J
Song
Lun
L
Zhang
Dongyun
D
Tong
Qiangsong
Q
Ding
Min
M
Bowman
Linda
L
Aziz
Robeena
R
Stoner
Gary D
GD
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D006224:Cricetinae; D004790:Enzyme Induction; D005638:Fruit; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D027824:Rosaceae; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D002273:Carcinogens; D010936:Plant Extracts; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa