MAAUA: MAAUA 68th Annual Meeting Abstracts - The Mechanism of Statin-Induced Autophagy in Prostate Cancer Cells

MAAUA 68th Annual Meeting Abstracts

The Mechanism of Statin-Induced Autophagy in Prostate Cancer Cells
Nicholas J Toepfer, *Chandra Childress, Ankur Parikh, Daniel B Rukstalis, *Wannian Yang
Geisinger Medical Center, Danville, PA

Introduction: Our previous studies have demonstrated that atorvastatin, an inhibitor of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, induces autophagy in the prostate cancer cell line PC3 through inhibition of geranylgeranyl biosynthesis. This study attempts to elucidate the molecular mechanism by which inhibition of geranylgeranyl biosynthesis induces autophagy.
Methods: PC3 cells were treated with atorvastatin, plus a protein translational inhibitor (cyclohexamide), transcriptional inhibitor (chromomycin A), c-JUN kinase inhibitor (SP600125), p38 kinase inhibitor (SB203580), or MEK inhibitor (U0126), and the protein expression level of autophagosomal marker LC3-II and the mRNA level of LC3 were determined by immnoblot analysis and RT-PCR assay. PC3 cell survival following treatment with atorvastatin plus cyclohexamide or chromomycin A was studied. The effect of atorvastatin on gene expression profile in PC3 cells was determined by the DNA microarray assay.
Results: The atorvastatin-induced LC3-II expression was inhibited by both cyclohexamide and chromomycin A, suggesting that atorvastatin activates transcription of LC3. Consistent with this, atorvastatin enhanced the expression of LC3 mRNA. Addition of geranylgeraniol to atorvastatin eliminates the enhancement of LC3 mRNA, confirming the activation of LC3 transcription is dependent on inhibition of geranylgeranyl biosynthesis. Further, SP600125 and U0126 inhibited the atorvastatin-induced expression of LC3-II. The DNA microarray assay demonstrated that inhibition of geranylgeranyl biosynthesis by atorvastatin caused a dramatic change in expression of genes that regulate cell growth and division in PC3 cells.
Conclusions: Atorvastatin-caused inhibition of geranylgeranyl biosynthesis activates transcription of LC3 and elevates the LC3-II expression level through the JNK and ERK signaling pathways.

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