Induction of a Ribotoxic Stress Response That Stimulates Stress-Activated Protein Kinases by 13-Deoxytedanolide, an Antitumor Marine Macrolide
Induction of a Ribotoxic Stress Response That Stimulates Stress-Activated Protein Kinases by 13-Deoxytedanolide, an Antitumor Marine Macrolide
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DOI：
10.1271/bbb.70.161
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发表时间：
2006-01
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影响因子：
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通讯作者：
Kun-Hyung Lee;S. Nishimura;S. Matsunaga;N. Fusetani;H. Ichijo;S. Horinouchi;Minoru Yoshida
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作者：
Kun-Hyung Lee;S. Nishimura;S. Matsunaga;N. Fusetani;H. Ichijo;S. Horinouchi;Minoru Yoshida
13-脱氧脱氧丹内酯是从海绵中分离出来的一种结构独特、抗肿瘤活性强的大环内酯类化合物。最近，我们在体外发现13-脱氧丹内酯与酵母核糖体的大亚基结合并抑制多肽延伸，但其发挥抗肿瘤活性的机制尚不清楚。在这里，我们发现13-脱氧丹内酯强烈诱导纤溶酶原激活物抑制剂1 （PAI-1）启动子衍生的基因表达。与tgf - β不同，13-脱氧脱氧丹内酯并未引起Smad2/3的明显核易位，但它在非允许温度下将小鼠p53的温度敏感突变体（p53Val153）从细胞质重新定位到细胞核，这表明13-脱氧丹内酯抑制蛋白质合成。事实上，该药物在低纳摩尔浓度下抑制体内蛋白质合成，并强烈激活应激激活的蛋白激酶，如p38丝裂原激活蛋白激酶和Jun nh2末端蛋白激酶（JNK）。大霉素是一种众所周知的能激活p38和JNK的核素毒性应激诱导剂，它也能激活PAI-1基因的表达，而其他不能激活这些激酶的蛋白质合成抑制剂则不能。p38特异性抑制剂SB202190和p38和JNK抑制剂SP600125可阻断PAI-1基因在13-脱氧丹酚内酯和大霉素中的表达。13-脱氧脱氧胆甾醇和大霉素可激活p38和JNK上游的凋亡信号调节激酶1、MKK3/MKK6和SEK1/MKK4。这些结果表明，与大霉素一样，13-脱氧丹内酯可触发核毒性应激反应，激活应激激活的蛋白激酶级联反应，从而诱导PAI-1基因表达和细胞凋亡。
13-Deoxytedanolide is a structurally unique macrolide with strong antitumor activity isolated from a marine sponge. Recently, we showed that 13-deoxytedanolide bound to the large subunit of the yeast ribosome and inhibited polypeptide elongation in vitro, but the mechanism by which it exerts antitumor activity is still unknown. Here we show that 13-deoxytedanolide strongly induces plasminogen activator inhibitor 1 (PAI-1) promoter-derived gene expression. 13-Deoxytedanolide, unlike TGF-beta, did not cause apparent nuclear translocation of Smad2/3, but it relocalized the temperature-sensitive mutant of mouse p53 (p53Val153) from the cytoplasm to the nucleus at a nonpermissive temperature, suggesting that 13-deoxytedanolide inhibits protein synthesis. Indeed, the drug inhibited in vivo protein synthesis at low nanomolar concentrations and strongly activated stress-activated protein kinases such as p38 mitogen-activated protein kinase and Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that activates both p38 and JNK, also activated PAI-1 gene expression, while other protein synthesis inhibitors that do not activate the kinases failed to do so. PAI-1 gene expression by 13-deoxytedanolide and anisomycin was blocked by SB202190, a specific inhibitor of p38, and SP600125, an inhibitor of both p38 and JNK. 13-Deoxytedanolide and anisomycin caused activation of apoptosis signal-regulating kinase 1, MKK3/MKK6, and SEK1/MKK4, the regulatory kinases upstream of p38 and JNK. These results suggest that 13-deoxytedanolide, like anisomycin, triggers a ribotoxic stress response that activates stress-activated protein kinase cascades, thereby inducing PAI-1 gene expression and apoptosis.