TAUTOMYCIN - AN INHIBITOR OF PROTEIN PHOSPHATASE-1 AND PHOSPHSTASE-2A BUT NOT A TUMOR PROMOTER ON MOUSE SKIN AND IN RAT GLANDULAR STOMACH
TAUTOMYCIN - AN INHIBITOR OF PROTEIN PHOSPHATASE-1 AND PHOSPHSTASE-2A BUT NOT A TUMOR PROMOTER ON MOUSE SKIN AND IN RAT GLANDULAR STOMACH
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DOI：
10.1007/bf01197780
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发表时间：
1995-09-01
影响因子：
3.6
通讯作者：
FUJIKI, H
中科院分区：
文献类型：
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作者：
SUGANUMA, M;OKABE, S;FUJIKI, H
从螺旋轮枝链霉菌中分离出的他莫霉素是蛋白磷酸酶1和2A的抑制剂。在人角质形成细胞（PHK 16-I细胞）中，他莫霉素诱导的细胞角蛋白肽的过度磷酸化比冈田酸弱30倍。在用7，12-二甲基苯并[a]蒽启动的小鼠皮肤两阶段致癌实验中，重复应用互变霉素（30 μ g，40 nmol/应用）不会诱导肿瘤促进，而作为对照的冈田酸（1 μ g，1.2 nmol/应用）强烈诱导肿瘤促进。对于大鼠腺胃粘膜，互变霉素诱导鸟氨酸脱羧酶4 h后，胃插管。接下来在用N-甲基-N '-硝基-N-亚硝基胍（MNNG）引发的腺胃中研究互变霉素的肿瘤促进活性。从实验的第9周至第52周，在饮食中给予互变霉素（1 mg大鼠（-1）天（-1）），抑制而不是增强MNNG引发的腺胃中的肿瘤发展。52周时，MNNG+互变霉素组、MNNG单药组和互变霉素单药组的荷瘤率分别为20.0%、40.6%和0%。研究了与肿瘤坏死因子α（TNF α）（一种内源性肿瘤促进剂）相关的互变霉素无肿瘤促进活性的原因。我们发现，互变霉素既不增强小鼠皮肤中TNF α mRNA的表达，也不诱导人胃癌细胞系（KATO III细胞）中TNF α的释放，而冈田酸两者都有。这些结果表明，并非所有的蛋白磷酸酶抑制剂都是肿瘤促进剂，并表明冈田酸类化合物的肿瘤促进作用是由TNF α介导的。
Tautomycin isolated from Streptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 mu g, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 mu g, 1.2 nmol/application) application) as a control induced tumor promotion strongly. As for mucosa of rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Administration of tautomycin in the diet (1 mg rat(-1) day(-1)), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor alpha (TNF alpha), an endogenous tumor promoter. We found that tautomycin neither enhanced TNF alpha mRNA expression in mouse skin nor induced TNF alpha release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNF alpha.