Phenyl Acyl Acids Attenuate the Unfolded Protein Response in Tunicamycin-Treated Neuroblastoma Cells

Abstract

Understanding how neural cells handle proteostasis stress in the endoplasmic reticulum (ER) is important to decipher the mechanisms that underlie the cell death associated with neurodegenerative diseases and to design appropriate therapeutic tools. Here we have compared the sensitivity of a human neuroblastoma cell line (SH-SY5H) to the ER stress caused by an inhibitor of protein glycosylation with that observed in human embryonic kidney (HEK-293T) cells. In response to stress, SH-SY5H cells increase the expression of mRNA encoding downstream effectors of ER stress sensors and transcription factors related to the unfolded protein response (the spliced X-box binding protein 1, CCAAT-enhancer-binding protein homologous protein, endoplasmic reticulum-localized DnaJ homologue 4 and asparagine synthetase). Tunicamycin-induced death of SH-SY5H cells was prevented by terminal aromatic substituted butyric or valeric acids, in association with a decrease in the mRNA expression of stress-related factors, and in the accumulation of the ATF4 protein. Interestingly, this decrease in ATF4 protein occurs without modifying the phosphorylation of the translation initiation factor eIF2α. Together, these results show that when short chain phenyl acyl acids alleviate ER stress in SH-SY5H cells their survival is enhanced.

The therapeutic effects of 4-phenylbutyric acid in maintaining proteostasis

“…The authors concluded that 4-PBA protected against ER stress-induced but not mitochondriamediated cell death in this model (Qi et al, 2004). These findings are consistent with recent evidence suggesting that 4-PBA protected a neuroblastoma cell line from tunicamycin- (Zamarbide et al, 2013) and hydrogen peroxide- (Ye et al, 2014) induced UPR activation and cell death.…”

Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

“…ER stress and autophagy are other possible mechanisms of nanoparticle-induced toxicity [7,14,15]. In our study, we did not detect any changes in mRNA or protein levels of UPR markers HSPA5 (BiP), DDIT3 (CHOP) and XBP1s [33]. Although we found PM0.5 localized in structures similar to autophagosomes or late endosomal multivesicular bodies, autophagy was not induced in the PM0.5-exposed A549 cells (as determined by LC3B and p62 protein level and CYTO-ID ® marker).…”

“…ER stress leads to activation of genes involved in compensatory response, the UPR. We measured changes in HSPA5 (also known as binding immunoglobulin protein, BiP), DDIT3 (CHOP) and XBP1s mRNA and protein levels, representing activation of all three UPR pathways [33]. We found that, in contrast to commonly used ER stress inducers thapsigargin and tunicamycin, PM0.5 did not change mRNA levels of tested UPR-associated genes ( Figure 5).…”

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

“…7b, c). Tunicamycin has been reported to increase caspase-4 activity [18, 58] and reduce the viability of SH-SY5Y cells [16, 61]. We therefore measured cell viability of the cultured SH-SY5Y cells using CCK-8, a widely used assay that can sensitively measure the viability of a variety of cultured cells including SH-SY5Y cells [10, 56].…”