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Geldanamycin, a benzoquinone ansamycin, is a naturally occurring inhibitor of heat shock protein (Hsp90), which regulates the transcription activity of hypoxia inducible factor 1(HIF-1 α). Under hypoxia, HIF-1 α is activated in tumor cells, and induces the transcription of vascular endothelial growth factor (VEGF), which is the prime regulator for angiogenesis. VEGF promotes the formation of new blood vessels by stimulating endothelial cell division and migration. This eventually forms a vascular network that allows for tumor growth and metastasis. In this study, we used geldanamycin (GA) to inhibit HIF-1 alpha transcription function and VEGF secretion. Human prostate cancer DU145 cells were incubated in a hypoxic chamber at 1% O2 and 37C° for different times. HIF-1 α and VEGF had upregulated both their mRNA and protein levels under hypoxic conditions. We demonstrated that GA treatment of hypoxic DU145 cells abolished the induction of HIF-1α protein in a time-dependent manner and decreased VEGF mRNA and its protein levels. Similar results were obtained when DU145 cells incubated with 100 μ M of CoCl2and treated with GA. The evaluation of angiogenesis of GA treated or nontrated hypoxic DU145 cells was examined by using the chick chorioallantioic membrane (CAM). In addition, using conditioned medium from geldanamycin treated hypoxic cells led to a significant decrease in cell invasion in comparison with using conditioned medium from nontreated hypoxic cells. However, our results showed that there was no change in the levels of matrix metalloproteinases, MMP9 and MMP2 in GA treated or nontreated hypoxic cells. This data provides evidence for role of GA in inhibition of angiogenesis and also invasion mediated by HIF-1α in prostate cancer cells. (This work was supported by Canadian Institute of Health Research to G.S)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]