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.
Highlights
Atorvastatin belongs to a class of drugs known as statins, and is mainly used to lower serum cholesterol level by inhibiting the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) to mevalonate by HMG-CoA reductase, a rate-limiting step in the cholesterol biosynthesis pathway
When PC-3 cells were transfected with luciferase-reporter constructs containing antioxidant response element (ARE) site of NQO1 promoter, potential heat-shock response element/nuclear factor B (HSE)/NF-B site of p53 promoter, FOXO site of Bim promoter or E2F transcription factor 1 (E2F-1) consensus binding site and induced with atorvastatin for 48 hrs, 2-fold induction of ARE site was observed (Fig. 1)
To investigate which of the antioxidant response genes was induced by atorvastatin, total RNA was isolated from PC-3 and MCF-7 cells treated with atorvastatin, and expression of NQO1, Nrf2, heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2), glutathione S-transferase 1 (GSTM1) and UDP glucuronosyltransferase 1, polypeptide A1 (UGT1A1) was evaluated by RT-PCR using gene-specific primers
Summary
Atorvastatin belongs to a class of drugs known as statins, and is mainly used to lower serum cholesterol level by inhibiting the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) to mevalonate by HMG-CoA reductase, a rate-limiting step in the cholesterol biosynthesis pathway. This prevents the synthesis of downstream products such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate (GGPP), which are needed for post-translational activation (prenylation) of small GTPases such as Ras and Rho. Failure in the prenylation of these GTPases results in their inability to interact with a wide spectrum of functionally different downstream mediators to initiate cytoplasmic signalling pathways and to regulate cell cycle progression [1]. We report that atorvastatin up-regulates heme oxygenase-1 (HO-1) in PC-3 and MCF-7 cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
