Research Institute of Biomedical Engineering and Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Biochem Biophys Res Commun. 2010 Jul 16;398(1):68-73. doi: 10.1016/j.bbrc.2010.06.037. Epub 2010 Jun 15.
Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, many of these carcinostatic substances are toxic. Here, we show that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 arrest via the induction of p21(WAF1/CIP1) in a c-Myc, but not a p53, dependent manner. Ascochlorin has a broad spectrum of anti-tumor and anti-metastatic activities, but the molecular mechanism by which it inhibits cell cycle progression of cancer cells remains to be elucidated. We demonstrated that cytostatic G1 arrest by ascochlorin is mainly associated with the upregulation of p21(WAF1/CIP1), and the downregulation of c-Myc. Furthermore, we used a chromatin immunoprecipitation assay, RNA interference, and p53-deficient cells to verify that p21(WAF1/CIP1) induction by ascochlorin is related to transcriptional repression of c-Myc. Ascochlorin abolished pRB hyperphosphorylation, which resulted in the inactivation of E2F transcriptional activity. These results suggest that ascochlorin induces G1 arrest via the p53-independent suppression of c-Myc. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for c-Myc.
许多抗癌药物通过依赖 p53 的机制抑制细胞周期进程；然而，许多这些抗癌物质是有毒的。在这里，我们表明，穿心莲内酯，一种异戊二烯抗生素，通过诱导 p21(WAF1/CIP1)诱导 G1 期阻滞，是一种非毒性的抗癌剂，而不是依赖 c-Myc，但不依赖 p53。穿心莲内酯具有广谱的抗肿瘤和抗转移活性，但它抑制癌细胞细胞周期进程的分子机制仍有待阐明。我们证明，穿心莲内酯的细胞生长抑制性 G1 期阻滞主要与 p21(WAF1/CIP1)的上调和 c-Myc 的下调有关。此外，我们使用染色质免疫沉淀分析、RNA 干扰和 p53 缺陷细胞来验证穿心莲内酯诱导 p21(WAF1/CIP1)与 c-Myc 的转录抑制有关。穿心莲内酯消除了 pRB 的过度磷酸化，导致 E2F 转录活性的失活。这些结果表明，穿心莲内酯通过非依赖 p53 的方式抑制 c-Myc 诱导 G1 期阻滞。因此，我们揭示了穿心莲内酯通过 G1 期阻滞抑制肿瘤生长的作用，并确定了 c-Myc 的一种新的调节机制。
