Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription

Our previous studies have demonstrated that atorvastatin induces autophagy in the androgen receptor negative prostate cancer PC3 cells through inhibition of geranylgeranyl biosynthesis [Parikh et al., Prostate. 70(9): 971-981 (2010)]. This study attempts to elucidate the molecular mechanism underlying atorvastatin-induced autophagy in PC3 cells. PC3 cells were treated with atorvastatin, in combination with the inhibitors for transcription, protein translation, PI-3 kinase, mTOR, and MAP kinases. The atorvastatin-induced elevation of LC3-II was inhibited by both the translational and the transcriptional inhibitors, suggesting that the inhibition of geranylgeranyl biosynthesis by atorvastatin activates transcription of LC3, which results in elevation of LC3-II and activation of autophagy. RT-PCR and quantitative PCR assays showed that atorvastatin enhanced expression of LC3 mRNA, and addition of geranylgeraniol along with atorvastatin to the medium eliminated the enhancement, confirming the activation of transcription of LC3 is caused by atorvastatin-mediated inhibition of geranylgeranyl biosynthesis. Further, we found that both the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125, inhibited the atorvastatin-induced elevation of LC3-II, suggesting that the effect of atorvastatin on autophagy is mediated by the Erk and JNK pathways. Taken together, atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription.