Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

Abstract

Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.

Cell death induced by the ER stressor thapsigargin involves death receptor 5, a non-autophagic function of MAP1LC3B, and distinct contributions from unfolded protein response components

“…The specific regulation of DR5 and LC3B at the protein level may be equally or even more important than their regulation at the mRNA level. An exclusive regulation of DR5 at the protein level has been observed in response to glucose deprivation of HeLa cells, where DR5 protein levels rose in the 24-72 h time period in the absence of any increase in DR5 mRNA levels [77]. Under those conditions, the upregulation of DR5 protein levels was abolished upon silencing of ATF4, but not CHOP [77], whereas the putative role of PERK or other kinases of the integrated stress response was not examined.…”

“…It should be noted that those studies examined neither the protein expression levels nor the potential requirement for DR4, TNFR1, or Fas in ER stress-induced apoptosis. A recent study found that glucose deprivation (which induces many forms of cellular stress, including ER stress) could increase DR4 protein levels without increasing DR4 mRNA levels in HeLa cells, and glucose deprivation-induced cell death showed comparable dependencies on DR4 and DR5 [77]. Interestingly, our results showed that Fas was partially required for Tg-induced cell death in LNCaP, but not HCT116 cells, suggesting a corequirement for DR5 and Fas in ER stress-induced cell death in LNCaP cells (yet with the strongest dependency on DR5).…”

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

“…However, sustained stress changes the adaptive response to a prodeath response and ultimately, the phosphorylation status of eIF2α appears to codetermine the balance between prosurvival or prodeath signalling . This is accomplished by the above mentioned delayed feedback through which the interplay of GADD34, ATF4 and CHOP results in the activation of genes involved in cell death, cell‐cycle arrest and senescence (Fig. ).…”

“…CHOP activates transcription of BIM and PUMA, while it represses transcription of certain antiapoptotic BCL‐2 family members such as MCL‐1 . In addition, the ATF4/CHOP pathway can increase the expression of other proapoptotic genes, such as TRAIL‐R1/DR4 and TRAIL‐R2/DR5 which promote extrinsic apoptosis . Apart from CHOP, p53 is also involved in the direct transcriptional upregulation of BH3‑ only proteins during ER stress.…”

Antitumor Effect of Periplocin in TRAIL‐Resistant gastric cancer cells via upregulation of death receptor through activating ERK1/2‐EGR1 pathway

“…TRAIL binds DR4 and DR5 to activate FADD (Fas‐associating protein with a novel death domain), which induces activation of several proapoptotic and antiapoptotic proteins . As shown in Figure A, the expression levels of cleaved caspase‐3 and caspase‐8 was significantly increased in cells after treated with Periplocin and TRAIL, suggesting that combined treatment with Periplocin and TRAIL induced more gastric cancer cell apoptosis through the mitochondrial apoptosis pathway than treatment with TRAIL or Periplocin alone.…”