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Small Molecules that Suppress IGF-Activated Prostate Cancers
Final rept. 1 Apr 2003-31 Mar 2006
BAYLOR COLL OF MEDICINE HOUSTON TX
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Elevated serum levels of insulin-like growth factor 1 IGF1 have been found in prostate cancer patients, and IGF1-related signal transduction is thought to be an important factor in the development of prostate cancers. The goals of this project are to discover small organic molecules that suppress IGF-activated prostate cancers by cell-based screening and to analyze their action mechanisms. During the funding period, we discovered, from our collection of synthetic compounds, the drug-like compound we call 125B11 that suppress IGF1-dependent growth of prostate cancer cells but not serum-dependent growth. We analyzed the mechanism of action of 125B11 to gain molecular insights into how IGF1 stimulates the growth of prostate cancer cells. DNA microarray and molecular biological experiments indicated that 125B11 blocks the activation of sterol regulatory element binding protein SREBP, a transcription factor that activates specific genes involved in cholesterol synthesis, endocytosis of low density lipoproteins, and the synthesis of both saturated and unsaturated fatty acids. Our results suggest a novel crosstalk between fatcholesterol metabolism and prostate cancer progression.
APPROVED FOR PUBLIC RELEASE