Statin-induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells.
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.
Parikh
Ankur
A
Department of Urology, Geisinger Clinic, Danville, Pennsylvania, USA.
Childress
Chandra
C
Deitrick
Kelly
K
Lin
Qiong
Q
Rukstalis
Daniel
D
Yang
Wannian
W
D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D054876:Prenylation / Q000187:drug effects* / Q000502:physiology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin