Fujiki H, Suganuma M, Komori A, Yatsunami J, Okabe S, Ohta T, Sueoka E
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Detect Prev. 1994;18(1):1-7.
Tumor promotion is a critical point in multistage carcinogenesis in humans. We have identified a common biochemical and molecular tumor promotion mechanism, the okadaic acid pathway, applicable in various organs. Tumor promotion by the okadaic acid class of compounds is mediated through inhibition of protein phosphatases 1 and 2A, resulting in an increase of protein phosphorylation and a subsequent expression of cell proliferation genes. Recently, we demonstrated that okadaic acid induced the release of mouse tumor necrosis factor-alpha (mTNF-alpha) from BALB/3T3 cells. The first part of this review discusses the link between the okadaic acid pathway and TNF-alpha as endogenous tumor promoters in vivo. Inhibitors of tumor promotion are varied. For the purpose of cancer chemoprevention in humans, the inhibitors sarcophytol A, canventol, and (-)-epigallocatechin gallate (EGCG) were studied and the results are presented. The inhibitory mechanisms also were varied: sarcophytol A inhibited H2O2 formation by TPA-activated human polymorphonuclear leukocytes; canventol inhibited protein isoprenylation in the cells; and EGCG, which is a main constituent of Japanese green tea, is an antioxidant. These inhibitors are promising cancer chemopreventive agents. Study of the essential tumor promotion mechanisms will facilitate the development of cancer chemopreventive agents.
肿瘤促进是人类多阶段致癌过程中的一个关键点。我们已经确定了一种常见的生化和分子肿瘤促进机制，即冈田酸途径，它适用于各种器官。冈田酸类化合物的肿瘤促进作用是通过抑制蛋白磷酸酶1和2A介导的，导致蛋白质磷酸化增加以及随后细胞增殖基因的表达。最近，我们证明冈田酸可诱导BALB/3T3细胞释放小鼠肿瘤坏死因子-α（mTNF-α）。本综述的第一部分讨论了冈田酸途径与TNF-α作为体内内源性肿瘤促进剂之间的联系。肿瘤促进抑制剂多种多样。为了人类癌症化学预防的目的，对抑制剂A、坎文托和（-）-表没食子儿茶素没食子酸酯（EGCG）进行了研究并展示了结果。其抑制机制也各不相同：A抑制TPA激活的人多形核白细胞形成H2O2；坎文托抑制细胞中的蛋白质异戊二烯化；而EGCG作为日本绿茶的主要成分，是一种抗氧化剂。这些抑制剂是很有前景的癌症化学预防剂。对基本肿瘤促进机制的研究将有助于癌症化学预防剂的开发。
