Oncostatin M induces VEGF through regulation of HIF-1α

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2044 Oncostatin M (OSM), a gp130-multifunctional cytokine, has been shown to inhibit the proliferation of breast and other tumor cell line , and attention has been given to OSM as a potential cancer therapeutic. However, more recent studies have shown that OSM stimulates cell detachment and invasion and induces vascular endothelial growth factor (VEGF) in endothelial and astroglioma cells suggesting that OSM may play a role in angiogenesis and tumor progression. We demonstrate a novel property of OSM in the upregulation of hypoxia-inducible factor-1α (HIF-1α), a potent pro-angiogenic transcription factor necessary for the induction of VEGF. We subjected MDA-MB-231 and T47D human breast cancer cells to hypoxia or normoxia along with small molecule inhibitors to determine the mechanism of OSM-upregulated HIF-1α. We show that OSM inducement of HIF-1α is primarily through protein synthesis. In addition, we find that the expression of OSM-induced VEGF and HIF-1α is dependent on STAT3 involvement. Finally, unlike some gp130-cytokines, OSM appears to activate multiple signaling pathways necessary for the induction of VEGF. These results suggest the importance of designing therapeutics to inhibit OSM during breast cancer progression and subsequent metastasis.