National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea.
Cancer Res. 2010 Mar 1;70(5):1932-40. doi: 10.1158/0008-5472.CAN-09-3501. Epub 2010 Feb 23.
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.
大蒜的摄入与某些癌症的风险呈负相关。本研究旨在探讨大蒜成分二烯丙基三硫化物（DATS）对 12-O-十四烷酰佛波醇-13-醋酸酯（TPA）诱导的环氧合酶-2（COX-2）表达和肿瘤促进作用的影响，并探讨其潜在的分子机制。不同大蒜衍生的烯丙基硫化物预处理小鼠皮肤显示，DATS 是抑制 TPA 诱导的 COX-2 表达最有效的。DATS 显著抑制了 TPA 刺激的小鼠皮肤中激活蛋白-1（AP-1）的 DNA 结合，AP-1 是调节 COX-2 表达的转录因子之一。DATS 还减弱了 TPA 诱导的 c-Jun 和 c-Fos 的表达，AP-1 的主要成分，并减弱了 c-Jun NH（2）-末端激酶（JNK）和 Akt 的激活。分别用 SP600125 或 LY294002 抑制 JNK 或 Akt，导致 AP-1 的 DNA 结合减少，c-Jun 和 c-Fos 的水平降低，以及 COX-2 的表达在 TPA 处理的小鼠皮肤中受到抑制。用 c-Jun 融合蛋白作为底物的 JNK 或 Akt 激酶测定表明，TPA 诱导了小鼠皮肤中 JNK 或 Akt 介导的 c-Jun 磷酸化，这一过程被 DATS 或各自的药理抑制剂显著减弱。评价 DATS 对 7,12-二甲基苯并（a）蒽引发和 TPA 促进的小鼠皮肤致癌作用的抗肿瘤促进作用的评价表明，DATS 预处理显著降低了乳头状瘤的发生率和多发性。综上所述，DATS 通过调节 JNK 或 Akt 信号通路对 TPA 诱导的 AP-1 激活和 COX-2 表达的抑制作用，可能部分解释了其对小鼠皮肤癌变的抗肿瘤促进作用。
