C-FLIP is a target of the E3 ligase deltex1 in gastric cancer
Journal
Cell Death and Disease
Journal Volume
9
Journal Issue
2
Pages
135
Date Issued
2018
Author(s)
Abstract
The ubiquitin E3 ligase DELTEX1 (DTX1) is specifically downregulated in gastric cancer tissues, and expression of DTX1 is linked to better prognoses and survival in gastric cancer. Cellular FLICE inhibitory protein (c-FLIP) is known for its pivotal role in the resistance of cancer cells to death receptor-induced cell death. Here, we show that DTX1 is an E3 ligase for c-FLIP in gastric cancer cells. DTX1 promoted c-FLIP downregulation. Overexpression of DTX1 sensitized gastric cancer cells to TRAIL-induced apoptosis, whereas DTX1-knockdown attenuated apoptosis induction. DTX1 binds c-FLIP L and directs it into the endosome-lysosomal pathway for proteasome-independent degradation. Moreover, induction of DTX1 in AGS cells by geldanamycin conferred susceptibility of those cells to TRAIL-induced apoptosis. Our results reveal a tumor-suppressive role for DTX1 and suggest a new approach to increasing TRAIL efficacy by raising DTX1 levels in gastric cancer therapy. DTX1 also enhanced c-FLIP degradation and FasL-induced and TRAIL-induced apoptosis in T cells, suggesting that DTX1 constitutes one of the physiological mechanisms regulating c-FLIP stability. ? 2018 The Author(s).
SDGs
Other Subjects
FLICE inhibitory protein; geldanamycin; protein deltex1; tumor necrosis factor related apoptosis inducing ligand; ubiquitin protein ligase E3; unclassified drug; benzoquinone derivative; DTX1 protein, human; Fas ligand; FLICE inhibitory protein; macrocyclic lactam; protein binding; tumor necrosis factor related apoptosis inducing ligand; ubiquitin protein ligase; AGS cell line; apoptosis; Article; controlled study; down regulation; endosome; gene overexpression; human; human cell; lysosome; priority journal; protein degradation; protein function; protein protein interaction; protein stability; protein targeting; signal transduction; stomach cancer; disease exacerbation; disease free survival; drug effect; metabolism; pathology; stomach tumor; tumor cell line; Apoptosis; Benzoquinones; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Disease Progression; Disease-Free Survival; Down-Regulation; Endosomes; Fas Ligand Protein; Humans; Lactams, Macrocyclic; Lysosomes; Protein Binding; Proteolysis; Stomach Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Ubiquitin-Protein Ligases
Publisher
Nature Publishing Group
Type
journal article