Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation
Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation
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DOI：
10.1038/sj.onc.1202275
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发表时间：
1999-01-07
期刊：
影响因子：
8
通讯作者：
Mizutani, S
中科院分区：
文献类型：
--
作者：
Iwata, S;Sato, Y;Mizutani, S
由生长因子刺激或由致癌物、病毒或癌基因诱导的细胞增殖和转化的特征在于多胺水平的相关增加，这是由多胺生物合成增加和多胺摄取增加介导的。多胺生物合成特别是在鸟氨酸脱羧酶（ODC）水平上被催化，另一方面，细胞多胺水平的升高加速了鸟氨酸脱羧酶抗酶（antizyme）的诱导，所述抗酶不仅参与ODC降解，而且参与多胺转运的负调节。利用抗酶的这些特性，研究了抗酶作为具有抗细胞生长和抗肿瘤活性的因子的潜力。我们发现，抗酶可以诱导细胞死亡与细胞内多胺含量的快速下降。在p21 H-ras（瓦尔12）转化的NIH 3T3细胞和几种人恶性肿瘤细胞系（包括p53表达缺失的细胞系）中测试了异位表达的抗酶的可能的抗肿瘤活性，它们在体外显示出与未转化的NIH 3T3细胞一样敏感。体内抗肿瘤活性也使用接种有H-vas转化的NIH3T3细胞的裸鼠进行了测试，所述细胞已经用诱导型抗酶表达载体转染，结果表明，体内抗酶表达阻断了这些小鼠中的肿瘤形成。这些结果表明，异位抗酶表达是可能的治疗癌症，这是介导的ODC失活和细胞内多胺耗尽的治疗效益。
Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines, Polyamine biosynthesis is catalyzed particularly, in the level of ornithine decarboxylase (ODC), The elevation of cellular polyamine levels on the other hand accelerates the induction of ornithine decarboxylase antizyme (antizyme), which is involved not only in ODC-degradation, but in the negative regulation of polyamine transport. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was investigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro. The in vivo antitumor activity was also tested using nude mice inoculated with H-vas transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic benefit in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.