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

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.

Cepharanthine Enhances TRAIL-Mediated Apoptosis Through STAMBPL1-Mediated Downregulation of Survivin Expression in Renal Carcinoma Cells

“…We isolated total RNA using TRIzol reagent (Life Technologies, Gaithersburg, MD, USA), and cDNA was prepared using Moloney murine leukemia virus (M-MLV) reverse transcriptase (Gibco-BRL, Gaithersburg, MD, USA) [ 36 , 40 ].…”

Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

“…A number of in vitro experiments could show that the knockdown (KD) of 5-LO affects the growth and survival of cancer cell lines derived from solid tumors ( Romano et al, 2001 ; Tong et al, 2002 ; Ding et al, 2012 ; Woo et al, 2017 ; Monga et al, 2020 ; Li et al, 2021 ) and knockout of 5-LO influences the expression of proteins involved in cellular adhesion, extracellular matrix formation, and cytoskeleton organization, thereby affecting directed cell motility and tumor spheroid formation of cancer cell lines ( Weisser et al, 2022 ). Furthermore, 5-LO products are known to activate anti-apoptotic signaling pathways and promote tumor cell proliferation in vitro and metastasis and angiogenesis in vivo ( Boado et al, 1992 ; Hong et al, 1999 ; Avis et al, 2001 ; Romano et al, 2001 ; Chen et al, 2006 ).…”

Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization

“…In other cancers, inhibition of Cats alone has no effect on apoptosis but increases cell sensitivity to anti-cancer drugs. Inhibition of Cat S and Cat G enhances TRAIL-mediated apoptosis through the modulation of the expression of anti-apoptotic proteins [12,13], and inhibition of Cat L increases the rate of irradiation-mediated apoptosis [14,15]. In addition, inhibition of Cats enhances anti-cancer effects, including induction of apoptosis and inhibition of invasion and cell growth [[16], [17], [18], [19], [20], [21]].…”