p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc
p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc
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DOI：
10.1158/1535-7163.mct-09-1159
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Chang, Young-Chae
中科院分区：
文献类型：
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作者：
Jeong, Ji-Hak;Kang, Shin-Sung;Chang, Young-Chae
抗坏血酸呋喃酮已被证明具有抗肿瘤活性，但其抑制癌细胞增殖的精确分子机制仍不清楚。在这里，我们研究了Ascofuranone对人类癌细胞细胞周期进程的影响，发现Ascofuranone诱导G（1）停滞而无细胞毒性，上调p53和p21（WAF 1/CIP 1），同时下调c-Myc和G（1）细胞周期蛋白。对p53和p21缺陷细胞的染色质免疫沉淀试验和RNA干扰研究表明，Ascofuranone通过释放c-Myc介导的转录抑制的p21（WAF 1/CIP 1）启动子诱导p21（WAF 1/CIP 1）表达和随后的G（1）阻滞，而不依赖于p53。抗坏血酸呋喃酮诱导的p21（WAF 1/CIP 1）与CDK 2结合并阻止CDK 2-细胞周期蛋白E复合物的形成，导致E2 F转录活性失活。这些结果表明，Ascofuranone通过p53非依赖性抑制c-Myc表达上调p21（WAF 1/CIP 1），导致细胞生长抑制性G（1）阻滞。因此，Ascofuranone代表了一种独特的天然抗肿瘤化合物，其靶向c-Myc而不依赖于p53。Mol Cancer Ther; 9（7）; 2102-13. (C)2010年AACR。
Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G(1) arrest without cytoxicity with upregulation of p53 and p21(WAF1/CIP1) while downregulating c-Myc and G(1) cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21(WAF1/CIP1) expression and subsequent G(1) arrest through the release of p21(WAF1/CIP1) promoter from c-Myc-mediated transcriptional repression, independent of p53. Ascofuranone-induced p21(WAF1/CIP1) associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21(WAF1/CIP1) through p53-independent suppression of c-Myc expression, leading to cytostatic G(1) arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53. Mol Cancer Ther; 9(7); 2102-13. (C) 2010 AACR.