Abstract
Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.
Highlights
Cancer cells induce distinct alterations of metabolic pathways, including glycolysis and protein synthesis, to survive and proliferate under conditions of stress associated with tumor growth such as nutrient limitation and anaerobic stress [1,2,3]
To understand the role of p53 in the endoplasmic reticulum (ER) stress response mediated by the IRE1α/XBP1, activating transcription factor 6 (ATF6), and protein kinase R-like ER kinase/pancreatic eIF2 kinase (PERK)/eIF2α signaling pathways, we treated HCT116 p53+/+ and HCT116 p53−/− cells (Figure 1A), MEF p53+/+ and MEF p53−/− cells (Figure 1B), and U2OS-shLuc and U2OS-shp53 cells (Figure 1C) with inducers of ER stress, brefeldin A (BFA), tunicamycin (Tm), or both, to determine the expression of proteins that mediate the ER stress response. p53 deficiency obviously affected IRE1α expression level compare to p90ATF6 cleavage and phosphorylation of eIF2α by PERK upon ER stress (Figure 1A)
Basal IRE1α protein and spliced XBP1 mRNA levels were moderately elevated in the absence of ER stress agents, suggesting that does loss of p53 function potentiates the IRE1α/XBP1 pathway of the unfolded protein response (UPR) upon ER stress but p53 function may have an inhibitory effect on the pathway
Summary
Cancer cells induce distinct alterations of metabolic pathways, including glycolysis and protein synthesis, to survive and proliferate under conditions of stress associated with tumor growth such as nutrient limitation and anaerobic stress [1,2,3]. Cancer cells synthesize a large amount of protein to support their rapid growth [4]. Metabolic and anaerobic stress induce ER dysfunction and the unfolded protein response (UPR). UPR maintains and restores ER homeostasis by increasing protein secretion through induction of ER chaperons that mediate protein refolding and by degrading unfolded proteins. Increasing the function of ER and its resistance to ER stress is essential for tumor proliferation and survival, and these processes are implicated in the enhancement of ER function in diverse types of human cancer cells [5, 6]
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