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

// Hyun Joo Jang 1 , Eun Mi Hong 1 , Mikang Kim 1 , Jae Hyun Kim 1 , Juah Jang 1 , Se Woo Park 1 , Hyun Wu Byun 2 , Dong Hee Koh 1 , Min Ho Choi 1 , Sea Hyub Kae 1 , Jin Lee 1 1 Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Gyeonggi do, Korea 2 Division of Gastroenterology, Department of Internal Medicine, Hangang Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Korea Correspondence to: Hyun Joo Jang, email: jhj1229@hallym.or.kr Jin Lee, email: jinlee@hallym.or.kr Keywords: statin, NF-E2-related factor, colon cancer, extracellular-signal-regulated kinase, heme oxygenase-1 Received: March 29, 2016      Accepted: May 29, 2016      Published: June 15, 2016 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.