Atorvastatin activates heme oxygenase‐1 at the stress response elements

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.