410 ANTI-CANCER EFFICACY OF SIMVASTATIN ON PROSTATE CANCER CELLS AND TUMOR XENOGRAFTS IS MEDIATED THROUGH INHIBITION OF AKT (2011)

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011410 ANTI-CANCER EFFICACY OF SIMVASTATIN ON PROSTATE CANCER CELLS AND TUMOR XENOGRAFTS IS MEDIATED THROUGH INHIBITION OF AKT Samith Thomas Kochuparambil, Belal Al-Husein, Anna Goc, Martha Terris, and Payaningal R. Somanath Samith Thomas KochuparambilSamith Thomas Kochuparambil Augusta, GA More articles by this author , Belal Al-HuseinBelal Al-Husein Augusta, GA More articles by this author , Anna GocAnna Goc Augusta, GA More articles by this author , Martha TerrisMartha Terris Augusta, GA More articles by this author , and Payaningal R. SomanathPayaningal R. Somanath Augusta, GA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.499AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Statins inhibit HMG-CoA reductase, a rate liming enzyme in cholesterol synthesis. Growing body of evidences suggest that statins have the potential to reduce the risk of cancers. In prostate cancer cells, simvastatin is known to induce apoptosis. Our “central hypothesis” is that treatment with simvastatin will inhibit Akt affecting prostate cancer cell function, tumor growth and metastasis. If proven valid, it is likely that prostate tumor growth and metastasis can be down-regulated therapeutically utilizing simvastatin using a novel “Drug-repurposing strategy”. METHODS In the current study, we sought to investigate the pleiotropic effects of simvastatin on major signaling pathways in prostate cancer cells with respect to the regulation of cellular functions such as migration, proliferation, colony/foci formation and invasion, along with its already known effects on apoptosis. RESULTS Time- and dose-effects of simvastatin on LNCaP (androgen-dependent) and PC3 (androgen-independent) cells indicated that treatment with as low as 25μM simvastatin was sufficient to inhibit serum-stimulated activation of Akt-mTOR and cRaf-ERK pathways. Akin to this, treatment with 25μM simvastatin significantly inhibited serum- and EGF-induced cell migration, invasion, colony formation and proliferation. Simvastatin-mediated effects on cell migration and colony formation was rescued by Adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in androgen-independent prostate cancer cells lines such as PC3 and LnCAP C4-2. A xenograft model performed in nude mice exhibited reduced PC3 prostate tumor growth with simvastatin treatment (2mg/kg body weight/twice a day for 2 weeks) demonstrating the therapeutic potential of simvastatin for prostate cancer therapy. CONCLUSIONS Our findings suggest a link between simvastatin and Akt in the regulation of prostate cancer. Further investigation is currently underway in our laboratory to unravel the molecular mechanisms on simvastatin-mediated effects on prostate cancer in vivo using TRAMP+ transgenic mice. We also plan to undertake a clinical study on patients with prostate cancer who were on statin treatment prior to and after diagnosis and analyze biopsy specimen from these patients. A prospective study will look at the role of statins in prostate cancer prevention and/or on management. Our ultimate aim is to investigate if statins can be used as an adjuvant drug in the treatment of patients already diagnosed with prostate cancer. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e165 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.Metrics Author Information Samith Thomas Kochuparambil Augusta, GA More articles by this author Belal Al-Husein Augusta, GA More articles by this author Anna Goc Augusta, GA More articles by this author Martha Terris Augusta, GA More articles by this author Payaningal R. Somanath Augusta, GA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...