Use of simvastatin to inhibit advanced prostate cancer formation in the TRAMP mouse model of prostate cancer
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] A provocative question currently proposed by the NIH is: do statin medications, which lower serum cholesterol, prevent cancer? We hypothesize that statins work by lowering oxysterol concentrations. Oxysterols are oxygenated derivatives of cholesterol, which can bind to the Estrogen Receptors (ERs) and can stimulate Hedgehog (Hh) signaling. The interaction between the Estrogen Receptors (ERs) and hedgehog (Hh) signaling in prostate cancer (PCa) is a novel interface to target and treat advanced PCa. With 1 in 6 men in the United States developing PCa during their lifetime, understanding the etiology of the disease will help characterize new treatments. While endocrine therapies are often used as part of prostate cancer treatment regimens, their influence on Hh signaling in the prostate has not been elucidated. We have shown that several estrogenic compounds including 17[beta]-estradiol (E2), tamoxifen citrate, diethylstilbestrol, and diarylpropionitrile can inhibit Gli1-luciferase activity. In addition E2 can inhibit Gli1 protein concentrations and mRNA in the mouse TRAMP-C2 prostate cancer cell line. Thus endocrine treatments that alter the estrogen to androgen ratio may work in part due to their effect on hedgehog signaling. While endocrine treatments are common, there is currently a debate in the literature on the efficacy of using statins, cholesterol lowering medications, to prevent PCa. Epidemiological evidence suggests that statin usage will lower the incidence of advance prostate cancer in humans. The mechanism is unknown, and we hypothesize that statins work by lowering oxysterol concentrations. Oxysterols, oxygenated derivatives of cholesterol, are found most commonly in the LDL fraction of cholesterol. As statins particularly lower LDL cholesterol, we hypothesize they are reducing oxysterol concentrations in serum. We have shown here in cell culture studies that a variety of statins themselves can inhibit hedgehog signaling, monitored by Gli1-luciferase activity. In addition most oxysterols do not stimu
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