Phenyl acyl acids attenuate the unfolded protein response in tunicamycin-treated neuroblastoma cells.

Marta Zamarbide,Rafael Franco,Alberto Pérez-Mediavilla,Tomás Aragón,Ana Ricobaraza,Eva Martinez-Pinilla

doi:10.1371/journal.pone.0071082

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.

Highlights

The administration of 4-phenylbutyrate (PBA) is indicated as adjunct therapy in the chronic management of patients with disorders of the urea cycle that involve deficiencies of either carbamoylphosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase [1,2]
It was recently shown that PBA protects against endoplasmic reticulum (ER) stressinduced neuronal cell death [14], an effect that was correlated with a marked increase in H3 histone acetylation and a decrease in the expression of glucose-regulated protein 94 (GRP94), whose transcription augments in response to defects in N-linked glycosylation [15]
The effect of the ER stress inducer, tunicamycin, on cell death measured by the lactate dehydrogenase (LDH) activity released to the culture medium was assayed in human neuroblastoma SH-SY5H cells

Summary

Introduction

The administration of 4-phenylbutyrate (PBA) is indicated as adjunct therapy in the chronic management of patients with disorders of the urea cycle that involve deficiencies of either carbamoylphosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase [1,2]. PBA is potentially beneficial in the treatment of sickle cell disease, thalassemia, cancer, cystic fibrosis, spinal muscular atrophy, amyotrophic lateral sclerosis and type 2 diabetes mellitus [3,4,5,6,7,8,9,10,11]. In these pathologies, PBA appears to enhance both gene transcription and protein synthesis due to its properties as an histone deacetylase (HDAC) inhibitor [12]. It was recently shown that PBA protects against ER stressinduced neuronal cell death [14], an effect that was correlated with a marked increase in H3 histone acetylation and a decrease in the expression of glucose-regulated protein 94 (GRP94), whose transcription augments in response to defects in N-linked glycosylation [15]

Methods

Results

Conclusion