Antihepatoma Activity of Chaetocin Due to Deregulated Splicing of Hypoxia-Inducible Factor 1α Pre-mRNA in Mice and In Vitro
Antihepatoma Activity of Chaetocin Due to Deregulated Splicing of Hypoxia-Inducible Factor 1α Pre-mRNA in Mice and In Vitro
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DOI：
10.1002/hep.24010
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发表时间：
2011-01-01
期刊：
影响因子：
13.5
通讯作者：
Park, Jong-Wan
中科院分区：
文献类型：
--
作者：
Lee, Yoon-Mi;Lim, Ji-Hong;Park, Jong-Wan
毛壳素是一种由毛壳属真菌产生的抗生素，最近发现具有抗骨髓瘤活性。在这里，我们研究是否毛壳素对实体瘤有抗癌活性。毛壳素对小鼠和人肝癌裸鼠移植瘤的生长有抑制作用。免疫组织化学分析显示，毛壳素抑制缺氧诱导因子-1 α（HIF-1 α）的表达和血管形成的肿瘤。在移植于小鼠的HIF-1 α（+/+）纤维肉瘤中，毛壳素也显示出抗血管生成的抗癌活性，但在HIF-1 α（-/-）纤维肉瘤中没有。生化分析表明，毛壳素下调HIF-1 α和HIF-1靶基因的转录，包括血管内皮生长因子在肝癌组织和各种肝癌细胞系。根据文献报道，不成功的努力，以确定毛壳素的作用机制。出乎意料的是，发现毛壳素引起HIF-1 α前信使RNA（pre-mRNA）的积累，但降低肝癌细胞和组织中成熟mRNA的水平。在正常细胞衍生的细胞系中没有观察到毛壳素的这种作用，并且即使在癌细胞系中也是细胞类型依赖性的。结论：我们的研究结果表明，毛壳素可以开发作为一种抗癌剂靶向HIF-1在一些癌症，包括肝癌。这也表明，HIF-1 α前mRNA剪接是一种新的治疗靶点，用于控制HIF-1介导的病理过程。（肝脏学2011;53：171-180）
Chaetocin, an antibiotic produced by Chaetomium species fungi, was recently found to have antimyeloma activity. Here we examined whether chaetocin has anticancer activities against solid tumors. Chaetocin inhibited the growth of mouse and human hepatoma grafts in nude mice. Immunohistochemical analyses revealed that chaetocin inhibits hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression and vessel formation in the tumors. Chaetocin also showed antiangiogenic anticancer activities in HIF-1 alpha(+/+) fibrosarcoma grafted in mice, but not in HIF-1 alpha(-/-) fibrosarcoma. Biochemical analyses showed that chaetocin down-regulated HIF-1 alpha and the transcripts of HIF-1 target genes including vascular endothelial growth factor in hepatoma tissues and in various hepatoma cell lines. Based on the reported literature, unsuccessful efforts were made to determine the mechanism underlying the action of chaetocin. Unexpectedly, chaetocin was found to cause the accumulation of HIF-1 alpha premessenger RNA (pre-mRNA) but to reduce mature mRNA levels in hepatoma cells and tissues. Such an effect of chaetocin was not observed in cell lines derived from normal cells, and was cell type-dependent even among cancer cell lines. Conclusions: Our results suggest that chaetocin could be developed as an anticancer agent to target HIF-1 in some cancers including hepatoma. It is also suggested that the HIF-1 alpha premRNA splicing is a novel therapeutic target for controlling HIF-1-mediated pathological processes. (HEPATOLOGY 2011;53:171-180)