Abstract
Endoplasmic reticulum (ER) stress elicits the unfolded protein response (UPR), initially aimed at coping with the stress, but triggering cell death upon further stress. ER stress induces the C/EBP-® variant Liver-enriched Activating Protein (LAP), followed by the dominant-negative variant, Liver Inhibitory Protein (LIP). However, the distinct role of LAP and LIP in ER stress is unknown. We found that the kinetics of the ER stress-induced expression of LIP overlapped with that of the cell death in mouse B16 melanoma cells. Furthermore, inducible over-expression of LIP augmented ER stress-triggered cell death whereas over-expression of LAP attenuated cell death. Similar results were obtained in human 293T cells. Limited vasculature in tumors triggers hypoxia, nutrient shortage and accumulation of toxic metabolites, all of which eliciting continuous ER stress. We found that LAP promoted and LIP inhibited B16 melanoma tumor progression without affecting angiogenesis or accelerating the cell cycle. Rather, LAP attenuated, whereas LIP augmented tumor ER stress. We therefore suggest that C/EBP-® regulates the transition from the protective to the death–promoting phase of the UPR. We further suggest that the over-expression of LAP observed in many solid tumors promotes tumor progression by attenuating ER stress–triggered tumor cell death.
Highlights
The endoplasmic reticulum is the site of post-translational processing of secreted and cytoplasmic membrane proteins
Our findings suggest that C/EBP-b has a key role in regulating the transition from protective to death promoting Unfolded Protein Response (UPR); Liver-enriched Activating Protein (LAP) attenuates and Liver Inhibitory Protein (LIP) augments cell death, and LAP contributes to tumor progression by attenuating Endoplasmic reticulum (ER) stress and subsequent cell death
Tumor progression depends on the ability of its cells to adapt to ER stress due to lagging development of the neovasculature, which lead to nutrient limitation, impaired clearance of toxic metabolites and hypoxia
Summary
The endoplasmic reticulum is the site of post-translational processing (refolding, glycosylation and oxidative disulfide bond formation) of secreted and cytoplasmic membrane proteins. The ER is the site of membrane biogenesis and helps maintain intracellular calcium ion and lipid homeostasis. Accumulation of client proteins or misfolded proteins, overload of free cholesterol, perturbations in calcium ion homeostasis, oxidative stress and xenobiotic toxins rapidly induce ER stress, which triggers an evolutionarily conserved cellular response, termed the Unfolded Protein Response (UPR) [1]. Initial UPR is aimed at coping with the stress by inducing ER chaperones and attenuating general protein translation. Persistent ER stress induces the expression of the C/EBP homologous protein (CHOP), which initiates the cell death machinery [2]. The mechanisms that regulate the transition from the protective phase to the death–promoting phase of the UPR are not known
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