Abstract HDM2 is a master regulator and plays an important role in Tumor angiogenesis. To confirm this hypothesis, we used wild type LNCaP and HDM2 transfected LNCaP-MST prostate cancer cells for our study. In the HDM2 transfected cells we observed 96% higher HDM2 protein expression compared to LNCaP cells. In general, HDM2 over expression has been reported to be a potential cause for p53 degradation in many cancer cells. To confirm this negative correlation, p53 level was observed in HDM2 transfected cells. Compared to the wild type cells, only 10% of the p53 level was found in the HDM2 transfected LNCaP-MST cells. This confirms our speculation that, HDM2 mediated degradation of p53 may occur in LNCaP-MST cells. Following HDM2 transfection, the VEGF level was also increased by 180% in LNCaP-MST cells compared to LNCaP cells. Since, previous studies have indicated that HIF-1α has a major role in inducing VEGF transcription, we determined the level of HIF-1α in both cells. In LNCaP-MST cells, nearly 90% higher HIF-1α protein level was observed, this might be due to the inhibition of both prolyl hydroxylase and factor inhibiting HIF (FIH) activity by HDM2, which are essential to hydroxylate HIF-1α in critical position. Once, hydroxylated, HIF-1α can no longer bind to p300 and induce VEGF transcription. In addition, an increase in the activated form of STAT3 (p-STAT3) causing elevated VEGF transcription has been previously reported in many cancer cells. Accordingly, the p-STAT3 protein expressions observed in HDM2 transfected LNCaP-MST cells were 15 folds higher compared to the non-transfected wild type LNCaP cells. A negative regulatory role of p53 in controlling the levels of active STAT3 has also been previously reported in prostate cancer cell lines. Hence, it is suggested that HDM2 might be inducing the expression of active STAT3 by degrading p53 protein in LNCaP-MST cells. Overall, our results demonstrate that HDM2 has an important role in regulating the VEGF transcription via modulating HIF-1α and STAT3 protein expressions. We thank the Royal Dames of Fort Lauderdale, Inc. for their support. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B4.