Regulation of autophagy by ceramide-CD95-PERK signaling

Abstract

The manuscripts by Park et al.1 and Zhang et al.2 were initially planned as studies to understand the regulation of cell survival in transformed cells treated with sorafenib and vorinostat, and in primary hepatocytes treated with a bile acid+MEK1/2 inhibitor. In both cell systems we discovered that the toxicity of sorafenib and vorinostat or bile acid+MEK1/2 inhibitor exposure depended on the generation of ceramide and the ligand-independent activation of the CD95 death receptor, with subsequent activation of pro-caspase 8. We noted, however, in these systems that, in parallel with death receptor–induced activation of the extrinsic pathway, CD95 signaling also promoted increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2α, increased expression of ATG5, and increased processing of LC3 and vesicularization of a GFP-LC3 construct. The knockdown of ATG5 expression blocked GFP-LC3 vesicularization and enhanced cell killing. Thus ceramide-CD95 signaling promoted cell death via activation of pro-caspase 8 and cell survival via autophagy. PERK was shown to signal in a switch-hitting fashion; PERK promoted CD95-DISC formation and an eIF2α-dependent reduction in c-FLIP-s levels that were essential for cell killing to proceed, but in parallel it also promoted autophagy that was protective. The death receptor-induced apoptosis and autophagy occur proximal to the receptor rather than the mitochondrion, and the relative flow of death receptor signaling into either pathway may determine cell fate. Finally, death receptor induced apoptosis and autophagy could be potential targets for therapeutic intervention.

Modulation of pediatric brain tumor autophagy and chemosensitivity

“…Many publications report autophagy as a tumor cell killing mechanism by diverse anti-cancer agents [14][15][16]. However, autophagy induced during treatment often inhibits tumor cell killing as shown in our lab [17] and by others [18][19][20][21]. Thus there is evidence that autophagy can prevent or promote cancer and kill or protect cancer cells.…”

PERK Integrates Autophagy and Oxidative Stress Responses To Promote Survival during Extracellular Matrix Detachment

“…We reasoned that PERK and CHOP might have a different function in the luminal compartment. Because ECM detachment can induce autophagy (16) and PERK can activate autophagy (24,27,34), we first tested whether PERK activation in suspension was responsible for autophagy induction. The substratum detachment of MCF10A cells enhanced both PERK and eIF2␣ phosphorylation (Fig.…”

Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation

“…For instance, current literature supports the notion that ceramide-induced autophagy functions to promote cell death, either through the induction of autophagic cell death, 11,12 or by "switching" off autophagy and inducing apoptosis through the CAPN/calpain-mediated cleavage of ATG5, 13 and/or DISC formation. 14 Interestingly, acid sphingomyelinase (SMPD1), a hydrolase enzyme that is involved in sphingolipid metabolism reactions and is responsible for breaking sphingomyelin down into phosphocholine and ceramide, appeared to be responsible for the induction of autophagy during amino acid depletion, the prototypical preautophagic stimulus. 15 Recently, Hwang et al have demonstrated that gangliosides, sialic acid-containing glycosphingolipids, induce autophagic cell death of astrocytes by activation of the IKBKB/IKK-NFKB/ NF-kB pathway.…”