A novel role of c-FLIP protein in regulation of ER stress response

Abstract

Cellular-Flice-like inhibitory protein (c-FLIP) is an apoptosis modulator known to inhibit the extrinsic apoptotic pathway thus blocking Caspase-8 processing in the Death Inducing Signalling Complex (DISC). We previously demonstrated that c-FLIP localizes at the endoplasmic reticulum (ER) and that c-FLIP-deficient mouse embryonic fibroblasts (MEFs) display an enlarged ER morphology. In the present study, we have addressed the consequences of c-FLIP ablation in the ER stress response by investigating the effects of pharmacologically-induced ER stress in Wild Type (WT) and c-FLIP-/- MEFs. Surprisingly, c-FLIP-/- MEFs were found to be strikingly more resistant than WT MEFs to ER stress-mediated apoptosis. Analysis of Unfolded Protein Response (UPR) pathways revealed that Pancreatic ER Kinase (PERK) and Inositol-Requiring Enzyme 1 (IRE1) branch signalling is compromised in c-FLIP-/- cells when compared with WT cells. We found that c-FLIP modulates the PERK pathway by interfering with the activity of the serine threonine kinase AKT. Indeed, c-FLIP-/- MEFs display higher levels of active AKT than WT MEFs upon ER stress, while treatment with a specific AKT inhibitor of c-FLIP-/- MEFs subjected to ER stress restores the PERK but not the IRE1 pathway. Importantly, the AKT inhibitor or dominant negative AKT transfection sensitizes c-FLIP-/- cells to ER stress-induced cell death while the expression of a constitutively active AKT reduces WT cells sensitivity to ER stress-induced death. Thus, our results demonstrate that c-FLIP modulation of AKT activity is crucial in controlling PERK signalling and sensitivity to ER stress, and highlight c-FLIP as a novel molecular player in PERK and IRE1-mediated ER stress response.

FLIP as a therapeutic target in cancer

“…In the absence of FLIP, the PERK and IRE‐1 ER stress pathways were found to be compromised due to enhanced Akt activity. Restoring FLIP expression was sufficient to re‐sensitize the cells to ER stress and so, in this context at least, FLIP appears to have a pro‐death role . Interestingly, ER stress was also shown to downregulate FLIP, sensitizing cells to PERK‐dependent upregulation of TRAIL‐R2 .…”

“…In addition, there is evidence that downregulation of FLIP via JNK activation of ITCH may be mediated by ER stress‐dependent JNK/CHOP/TRAIL‐R2 signalling (Fig. ) .…”

Expression of ERO1L in gastric cancer and its association with patient prognosis

“…ERS was positively correlated with the depth of tumor invasion and degree of metastasis, indicating that ERS might be an important inducement of invasion and metastasis of tumor cells (26). ERS, a type of self-protective reaction of the cells, is involved in the occurrence and development of breast, liver and pancreatic cancer (27)(28)(29). ERO1L may promote the formation of a disulfide bond of unfolded protein and can maintain the appropriate oxidation environment of the endoplasmic reticulum as a redox sensor (30).…”

The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis

“…Downstream these three receptor activations signal cascades initiate at aiming to cope with the stress source. It is well established that some UPR mediators can directly participate in autophagy by connecting these two cellular mechanisms [90,91,92].…”

“…As a consequence, cellular senescence is induced in the biliary tree, impairing its functions in bile secretion and reabsorption. On the contrary, pretreatment with other types of bile acids, such as ursodeoxycholic acid (UDCA) and Tauro-UDCA, a chemical chaperone that increases the ER adaptive capacity, significantly decreases ER stress, autophagy and cellular senescence induced by GCDC [91]. Accordingly, UDCA is currently used as a standard treatment in primary biliary cirrhosis (PBC) since it acts as an anti-cholestatic, anti-fibrotic and anti-proliferative agent [93].…”