title: Atorvastatin activates heme oxygenase-1 at the stress response elements.
abstract: Statins are known to inhibit growth of a number of cancer cells, but their mechanism of action is not well established. In this study, human prostate adenocarcinoma PC-3 and breast adenocarcinoma MCF-7 cell lines were used as models to investigate the mechanism of action of atorvastatin, one of the statins. Atorvastatin was found to induce apoptosis in PC-3 cells at a concentration of 1 μM, and in MCF-7 cells at 50 μM. Initial survey of possible pathway using various pathway-specific luciferase reporter assays showed that atorvastatin-activated antioxidant response element (ARE), suggesting oxidative stress pathway may play a role in atorvastatin-induced apoptosis in both cell lines. Among the antioxidant response genes, heme oxygenase-1 (HO-1) was significantly up-regulated by atorvastatin. Pre-incubation of the cells with geranylgeranyl pyrophosphate blocked atorvastatin-induced apoptosis, but not up-regulation of HO-1, suggesting that atorvastatin-induced apoptosis is dependent on GTPase activity and up-regulation of HO-1 gene is not. Six ARE-like elements (designated StRE1 [stress response element] through StRE6) are present in the HO-1 promoter. Atorvastatin was able to activate all of the elements. Because these StRE sites are present in clusters in HO-1 promoter, up-regulation of HO-1 by atorvastatin may involve multiple StRE sites. The role of HO-1 in atorvastatin-induced apoptosis in PC-3 and MCF-7 remains to be studied.
authors: ORTD, Albert Einstein Medical Center, Philadelphia, PA 19141-3098, USA. kwoks@einstein.edu
authors: Simon C M
authors: SC
authors: Kwok
authors: Solomon P
authors: SP
authors: Samuel
authors: John
authors: J
authors: Handal
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006538:Heptanoic Acids; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D000069059:Atorvastatin; D051547:Heme Oxygenase-1; C002963:geranylgeranyl pyrophosphate