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

Abstract

Statin has been known not only as their cholesterol-lowering action but also on their pleiotropic effects including anti-inflammatory and anti-oxidant as well as anti-cancer effect. Nrf2 (NF-E2-related factor 2) is a transcription factor to activate cellular antioxidant response to oxidative stress. There are little known whether statins affect activation of Nrf2 and Nrf2 signaling pathway in colon cancer cells. We investigated whether simvastatin stimulates the expression of Nrf2 and nuclear translocation of Nrf2 and which signal pathway is involved in the expression of Nrf2 and antioxidant enzymes. We investigated the effect of simvastatin on the expression of Nrf2 and nuclear translocation of Nrf2 in two human colon cancer cell lines, HT-29 and HCT 116 through cell proliferation assay, Western blotting and immunocytochemical analysis. We evaluated which signal pathway such as ERK or PI3K pathway affect Nrf2 activation and whether simvastatin induces antioxidant enzymes (heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1), γ-glutamate-cysteine ligase catalytic subunit (GCLC)). We demonstrated simvastatin-induced dose-dependent up-regulation of Nrf2 expression and stimulated Nrf2 nuclear translocation in colon cancer cells. We also demonstrated that simvastatin-induced anti-oxidant enzymes (HO-1, NQO1, and GCLC) in HT-29 and HCT 116 cells. PI3K/Akt inhibitor (LY294002) and ERK inhibitor (PD98059) suppressed simvastatin-induced Nrf2 and HO-1 expression in both HT-29 and HCT 116 cells. This study shows that simvastatin induces the activation and nuclear translocation of Nrf2 and the expression of various anti-oxidant enzymes via ERK and PI3K/Akt pathway in colon cancer cells.

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

“…As previously demonstrated, Sim can activate Nrf2 in human melanoma cells and colon cancer cells [24]. Another study confirmed that Nrf2 is an important transcription factor involved in the anti-oxidant response [25] of cells, during which it binds to the anti-oxidant genes, HO-1 and NQO-1 [26].…”

Simvastatin attenuates renal ischemia/reperfusion injury from oxidative stress via targeting Nrf2/HO‑1 pathway

“…For instance, simvastatin was discovered to lower ROS levels by activating Nrf2 via the phosphoinositide-3 kinase (PI3K)/Akt pathway in ST-2 cells (33), to induce HO-1 via Nrf2 activation through the extracellular signal-regulated kinase and PI3K/Akt pathway in the HCT116 and HT-29 colon cancer cell lines (34), and to activate Keap1/Nrf2 signaling in rat liver primary hepatocytes (35). Taken together, it is possible to draw the conclusion that simvastatin upregulates HO-1 mRNA levels through activating the Nrf2 signaling pathway to ultimately protect the kidney from the I/R injury-associated oxidative stress response, renal tubule pathology and tubular epithelial cell apoptosis.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…In liver cirrhosis, simvastatin activates an axis formed by Krüppel-like factor 2 and NRF2 to reduce the oxidative burden and inflammatory response of stellate cells, improving liver fibrosis, endothelial dysfunction, and portal hypertension. The mechanism of activation of NRF2 by simvastatin is not completely clear, but it appears to involve elements found in the NRF2 interactome, such as mitogenactivated protein kinase, PI3K/AKT pathways (Jang et al, 2016), and GSK-3 (Lin et al, 2016).…”