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Statin‐inducedautophagy byinhibition ofgeranylgeranylbiosynthesis inprostate cancer PC3cells Ankur R. ParikhChandra ChildressKelly Deitrick2010 год

Statin‐induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells
статья из журнала

Страница публикацииПубликация в OpenAlex
Аннотация: Abstract BACKGROUND Autophagy is a cellular process of degradation of macromolecules and organelles and activated under nutritional stress. Statins are a class of inhibitors of 3‐hydroxyl‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, a key enzyme in synthesis of cholesterol. Epidemiological studies have shown that statin use decreases the incidence of advanced prostate cancer. We explored the idea that treatment of atorvastatin, a commonly prescribed statin for treatment of hypercholesterolemia, induces autophagy in prostate cancer cells. METHODS The atorvastatin‐induced autophagic process in prostate cancer PC3 cells was determined by detection of cellular level of LC3‐II, an autophagosomal marker, via immunoblotting and immunofluorescent staining. RESULTS Atorvastatin treatment of PC3 cells for 40 hrs increased expression of LC3‐II by more than 10 fold in a dose‐dependent manner. Treatment of the cells with pepstatin A and E64‐d, the autophagic protease inhibitors, dramatically increased atorvastatin‐dependent LC3‐II expression level, suggesting that atorvastatin induces autophagic flux. In addition, atorvastatin treatment caused rapid death of PC3 cells. Atorvastatin‐induced autophagy and rapid cell death were reversed by addition of geranylgeraniol, not farnesol, into culture medium, indicating that atorvastatin‐mediated inhibition of geranylgeranyl biosynthesis causes autophagy and cell death. Furthermore, atorvastatin did not induce autophagy or cell death in normal prostate RWPE1 cells, and induced only a minor autophagic response in AR‐positive prostate cancer LNCaP cells. CONCLUSIONS Our studies demonstrate that statins induce autophagy and autophagy‐associated cell death in PC3 cells, likely through inhibition of geranylgeranylation, and suggest that autophagic response to statins may partially underlie the protective effects of statins on prostate cancer progression. Importantly, these findings highlight additional mechanisms by which statins might be used for prostate cancer therapy. Prostate 70: 971–981, 2010. © 2010 Wiley‐Liss, Inc.
Год издания: 2010
Авторы: Ankur R. Parikh, Chandra Childress, Kelly Deitrick, Qiong Lin, Daniel B. Rukstalis, Wannian Yang
Издательство: Wiley
Источник: The Prostate
Ключевые слова: Cancer, Lipids, and Metabolism, Lipoproteins and Cardiovascular Health, Autophagy in Disease and Therapy
Другие ссылки: The Prostate (HTML)
PubMed (HTML)