title: Diallyl trisulfide inhibits phorbol ester-induced tumor promotion, activation of AP-1, and expression of COX-2 in mouse skin by blocking JNK and Akt signaling.
abstract: An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH(2)-terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK- or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.
authors.affiliation: National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Shrotriya
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors; D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D013440:Sulfides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000498:Allyl Compounds; D016861:Cyclooxygenase Inhibitors; D013440:Sulfides; D018808:Transcription Factor AP-1; C042577:diallyl trisulfide; D015127:9,10-Dimethyl-1,2-benzanthracene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D013755:Tetradecanoylphorbol Acetate