Presentation Abstract

Abstract Number: 3123
Presentation Title: Insulin-like Growth Factor-I Suppresses Bone Morphogenetic Protein Signaling through a Phosphatidylinositol 3-Kinase, Akt and mTOR-Dependant Mechanism
Presentation Time: Tuesday, Apr 20, 2010, 9:00 AM -12:00 PM
Location: Exhibit Hall A-C, Poster Section 7
Poster Section: 7
Poster Board Number: 9
Author Block: Reema S. Wahdan-Alaswad, Kyung Song, Tracy L. Krebs, David Danielpour. Case Western Reserve University, Cleveland, OH
Abstract Body: Bone morphogenetic proteins (BMPs) and insulin-like growth factor-I (IGF-I) function as critical regulators of prostate tumor cell growth. BMPs have recently been shown to be pivotal in controlling prostate tumorigenesis, and loss of BMP receptor function has been correlated to a higher Gleason grade in prostate cancer patients. The mechanism of such loss of BMP function in prostate cancer is unclear, and is likely to occur through multiple mechanisms. One likely candidate we are investigating is the tumor suppressor PTEN, which is lost up to 50% of patients with advanced prostate cancer. Loss of PTEN leads to enhanced activation of PI3K, Akt signaling and suppression of apoptosis. We provide the first evidence that IGF-I intercepts BMP4-induced apoptosis in prostate epithelial cell lines, as shown by changes in cell number, Hoechst 33342 staining, cell viability and flow cytometry. We show that IGF-I suppresses BMP4-induced activation of Smads 1, 5 and/or 8, and that such suppression is reversed by chemical inhibitors of PI3K, Akt or mTOR, or by wild-type PTEN or a dominant-negative PI3K expression construct efficiently delivered to cells by transduction adenoviral. We further show that IGF-I represses BMP4-induced transcriptional activation of the BMP targets, Id-1, Id-2, and Id-3. These results suggest that IGF-I signaling via a PI3K, Akt and mTOR-dependent mechanism inhibits transcriptional activity and apoptosis by BMP4 through suppressing the activation of Smads 1, 5 and/or 8 in prostate epithelial cells. All in all, our findings have important implications in the therapeutic intervention of prostate cancer by restoring BMP-mediated tumor suppressive capabilities by blocking IGF-I signaling pathway’s oncogenic activity.