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.

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

“…These effects were also caspase-dependent since simvastatin increased caspase-3 and -9 activity in MDA-MB231 cells39. Similarly, fluvastatin and atorvastatin, were also reported to induce dose- and time-dependent apoptosis in MCF-7 and MDA-MB-231 breast cancer cell lines4041. Several mechanisms have been proposed for statin-induced cell death in breast cancer cells including an increase of reactive oxygen species (ROS)42, the downregulation of survivin expression43, increased nitric oxide synthase activity (iNOS or NOS II) via geranylgeranylation44, and G1/S cell cycle arrest due to an increase in p21(Waf1/Cip1)45.…”

Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway

“…The enhancer-luciferase reporter plasmids were constructed by inserting sequences of various synthetic response elements into the filled-in Nhe I /Bgl II sites of pGL3-promoter vector (Promega, Madison, WI, USA) or Eco RV site of pGL4-promoter vector via blunt-end ligation as described in our earlier study [15]. Internal control plasmid, pGL4.74[hRluc/TK], was purchased from Promega (Madison, WI, USA).…”

“…In fact, it even suppressed the induction of HO-1 by statins or lipopolysaccharide [14]. In our earlier study, ZnPP was found to induce HO-1 expression in human prostate adenocarcinoma PC-3 and breast adenocarcinoma MCF-7 cells [15]. It is a much stronger inducer of HO-1 than atorvastatin, one of the statins.…”

Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer

“…They are also known to increase atherosclerotic plaque stability, to improve endothelial function and to have an anti-oxidant effect and anti-inflammatory activity [12]. According to some studies that investigate the antioxidant and anti-inflammatory effect of statins, atorvastatin activates heme oxygenase-1 at the stress response elements in prostatic cancer cells and breast cancer cells [13]. Simvastatin decreases reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway in primary mouse embryonic fibroblasts from wild-type or Nrf2 knockout C57BL6J mice and ST-2 cells [14].…”