Up-regulation of 5-lipoxygenase by inhibition of cathepsin G enhances TRAIL-induced apoptosis through down-regulation of survivin

Abstract

// Seon Min Woo 1, * , Kyoung-Jin Min 1, * , Seung Un Seo 1 , Shin Kim 1 , Jong-Wook Park 1 , Dae Kyu Song 2 , Hyun-Shik Lee 3 , Sang Hyun Kim 4 and Taeg Kyu Kwon 1 1 Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea 2 Department of Physiology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea 3 KNU-Center for Nonlinear Dynamics, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu 41566, South Korea 4 Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, South Korea * These authors contributed equally to this work Correspondence to: Taeg Kyu Kwon, email: kwontk@dsmc.or.kr Keywords: cathepsin G; TRAIL; survivin; ROS; 5-LOX Received: October 17, 2017      Accepted: November 01, 2017      Published: November 20, 2017 ABSTRACT Cathepsin G is a serine protease secreted from activated neutrophils, it has important roles in inflammation and immune response. Moreover, cathepsin G promotes tumor cell-cell adhesion and migration in cancer cells. In this study, we investigated whether inhibition of cathepsin G could sensitize TRAIL-mediated apoptosis in cancer cells. An inhibitor of cathepsin G [Cathepsin G inhibitor I (Cat GI); CAS 429676-93-7] markedly induced TRAIL-mediated apoptosis in human renal carcinoma (Caki, ACHN, and A498), lung cancer (A549) and cervical cancer (Hela) cells. In contrast, combined treatment with Cat GI and TRAIL had no effect on apoptosis in normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. Cat GI induced down-regulation of survivin expression at the post-translational level, and overexpression of survivin markedly blocked apoptosis induced by combined treatment with Cat GI plus TRAIL. Interestingly, Cat GI induced down-regulation of survivin via 5-lipoxygenase (5-LOX)-mediated reactive oxygen species (ROS) production. Inhibition of 5-LOX by gene silencing (siRNA) or a pharmacological inhibitor of 5-LOX (zileuton) markedly attenuated combined treatment-induced apoptosis. Taken together, our results indicate that inhibition of cathepsin G sensitizes TRAIL-induced apoptosis through 5-LOX-mediated down-regulation of survivin expression.