c-FLIP is a target of the E3 ligase deltex1 in gastric cancer

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-FLIPL 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.

The Ubiquitin Gene Expression Pattern and Sensitivity to UBB and UBC Knockdown Differentiate Primary 23132/87 and Metastatic MKN45 Gastric Cancer Cells

“…Finally, we looked for a molecular mechanism accounting for the reduced cell viability observed in the 23132/87 cells after the simultaneous silencing of poly-Ub genes UBC and UBB . Considering the role of the extrinsic pathway of apoptosis in gastric adenocarcinoma [ 39 ], we evaluated if the significant decrease ( p = 0.004) in 23132/87 cell viability after treatment with the combination si UBB +si UBC could be linked to an increase in Fas levels [ 31 ] and activation of caspase 3. As shown in Figure 5 C, si UBB +si UBC transfection in the 23132/87 cells led to a remarkable increase in the pro-apoptotic protein Fas and to a decrease in the inactive full-length caspase 3, indicating activation of the apoptotic process [ 28 ].…”

The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells

“…Therefore, the levels of death receptors and decoy receptors in cancer cells may affect TRAIL sensitivity. In addition, c-FLIP (cellular FLICE (FADD-like interleukin-1␤converting enzyme)inhibitory protein) is involved in the resistance of cancer cells to TRAIL-induced cell death (28,29). Levels of c-FLIP may affect the sensitivity of cancer cells to TRAIL (30).…”

E3 ubiquitin ligases in B-cell malignancies

“…Mechanically, Deltex has been shown to stimulate the degradation of many proteins such as MAP kinase kinase kinase 1 (MEKK1), protein kinase Cθ, phospholipase C-γ1, HIF-1α, and c-FLIP [87][88][89][90] . Deltex1 has also been shown to promote the expression of ILT3, the immunoglobulin-like transcript 3, in CLL.…”