Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF
| Autor: | Minoru Yoshida, Kazuyo Uchida, Ken Ishigami, Soichi Kojima, Misao Yoneyama, Ryohei Furumai, Yusuke Komi, Hidenori Watanabe |
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| Rok vydání: | 2010 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Angiogenesis Blotting Western Angiogenesis Inhibitors Chick Embryo Chorioallantoic Membrane HeLa Neovascularization chemistry.chemical_compound stomatognathic system Gene expression medicine Animals Humans Spiro Compounds Oligonucleotide Array Sequence Analysis Pyrans Messenger RNA Dose-Response Relationship Drug Molecular Structure Neovascularization Pathologic biology Reverse Transcriptase Polymerase Chain Reaction Alternative splicing General Medicine biology.organism_classification Molecular biology Gene Expression Regulation Neoplastic Vascular endothelial growth factor stomatognathic diseases Chorioallantoic membrane Oncology chemistry Cancer research medicine.symptom HeLa Cells |
| Zdroj: | Cancer Science. 101:2483-2489 |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/j.1349-7006.2010.01686.x |
| Popis: | Spliceostatin A (SSA) is a methylated derivative of an antitumor natural product FR901464, which specifically binds and inhibits the SF3b spliceosome sub-complex. To investigate the selective antitumor activity of SSA, we focused on the regulation of vascular endothelial growth factor (VEGF) mRNA, since VEGF is a key regulatory component in tumor angiogenesis and known for the intricate regulation of mRNA processing, such as alternative splicing. We found that in HeLa cells SSA reduced the amount of both mRNA and protein of VEGF. Spliceostatin A not only inhibited the splicing reaction of VEGF pre-mRNA but also reduced the total amount of VEGF’s transcripts, while SSA affected GAPDH mRNA to a lesser extent. Given a significant reduction in VEGF gene expression, SSA was expected to possess anti-angiogenic activity in vivo. Indeed, SSA inhibited cancer cell-derived angiogenesis in vivo in a chicken chorioallantoic membrane (CAM) assay. The inhibition of angiogenesis with SSA was abolished by addition of exogenous VEGF. We also performed global gene expression analyses of HeLa cells and found that the expression levels of 38% of total genes including VEGF decreased to |
| Databáze: | OpenAIRE |
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