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

Oncotarget 2017 Dec 20;8(63):106672-106684. Epub 2017 Nov 20.

Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu 704-701, South Korea.

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.

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.22508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739765PMC
December 2017

Publication Analysis

Top Keywords

down-regulation survivin
16
inhibition cathepsin
12
cancer cells
8
trail-induced apoptosis
8
treatment cat
8
combined treatment
8
cat induced
8
cat trail
8
trail-mediated apoptosis
8
survivin expression
8
induced down-regulation
8
apoptosis
7
cathepsin
6
cat
5
survivin
5
cells [mesangial
4
[mesangial cell
4
normal cells
4
fibroblast hsf]
4
expression post-translational
4

Similar Publications