Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1α pre-mRNA in mice and in vitro
Open Access
- 24 September 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 53 (1), 171-180
- https://doi.org/10.1002/hep.24010
Abstract
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‐1α (HIF‐1α) expression and vessel formation in the tumors. Chaetocin also showed antiangiogenic anticancer activities in HIF‐1α(+/+) fibrosarcoma grafted in mice, but not in HIF‐1α(−/−) fibrosarcoma. Biochemical analyses showed that chaetocin down‐regulated HIF‐1α 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‐1α 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‐1α pre‐mRNA splicing is a novel therapeutic target for controlling HIF‐1‐mediated pathological processes. (HEPATOLOGY 2011;.)Keywords
This publication has 26 references indexed in Scilit:
- Targeted therapy for hepatocellular carcinomaNature Reviews Gastroenterology & Hepatology, 2009
- Angiogenesis in liver diseaseJournal of Hepatology, 2009
- The role of hypoxia-inducible factors in tumorigenesisCell Death & Differentiation, 2008
- Hepatocellular Carcinoma: Epidemiology and Molecular CarcinogenesisGastroenterology, 2007
- Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9Nature Chemical Biology, 2005
- Targeting HIF-1 for cancer therapyNature Reviews Cancer, 2003
- Hypoxia — a key regulatory factor in tumour growthNature Reviews Cancer, 2002
- The fungal metabolite gliotoxin: immunosuppressive activity on CTL-mediated cytotoxicityImmunology Letters, 2000
- Studies on fungal products. Part XXXI. Structures of novel epipolythiodioxopiperazines, emethallicins B. C, and D. potent inhibitors of histamine release, from Emericella heterothallica.CHEMICAL & PHARMACEUTICAL BULLETIN, 1990
- Mycotoxin production by Chaetomium spp. and related fungiCanadian Journal of Microbiology, 1981