title: Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription.
abstract: 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.
authors.affiliation: Department of Urology, Geisinger Clinic, Danville, PA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Toepfer
authors.forename: Chandra
authors.initials: C
authors.lastname: Childress
authors.forename: Ankur
authors.initials: A
authors.lastname: Parikh
authors.forename: Daniel
authors.initials: D
authors.lastname: Rukstalis
authors.forename: Wannian
authors.initials: W
authors.lastname: Yang
mesh_terms: D000069059:Atorvastatin; D001343:Autophagy / Q000187:drug effects*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D004224:Diterpenes / Q000494:pharmacology; D057809:HEK293 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000069059:Atorvastatin; D004224:Diterpenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008869:Microtubule-Associated Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011758:Pyrroles; D058570:TOR Serine-Threonine Kinases; C477012:MAP1LC3A protein, human; C017338:geranylgeraniol; C546842:MTOR protein, human