ER stress and the unfolded protein response in intestinal inflammation

McGuckin, Michael A., Eri, Rajaraman D., Das, Indrajit, Lourie, Rohan and Florin, Timothy H. (2010) ER stress and the unfolded protein response in intestinal inflammation. American Journal of Physiology: Gastrointestinal and Liver Physiology, 298 6: G820-G832. doi:10.1152/ajpgi.00063.2010

Author McGuckin, Michael A.
Eri, Rajaraman D.
Das, Indrajit
Lourie, Rohan
Florin, Timothy H.
Title ER stress and the unfolded protein response in intestinal inflammation
Journal name American Journal of Physiology: Gastrointestinal and Liver Physiology   Check publisher's open access policy
ISSN 0193-1857
Publication date 2010-06-01
Year available 2010
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1152/ajpgi.00063.2010
Open Access Status Not Open Access
Volume 298
Issue 6
Start page G820
End page G832
Total pages 23
Place of publication Bethesda, MD, U.S.A.
Publisher American Physiological Society
Language eng
Subject 1303 Biochemistry
1307 Cell Biology
Abstract Although there have been advances in our understanding of carcinogenesis and development of new treatments, cancer remains a common cause of death. Many regulatory pathways are incompletely understood in cancer development and progression, with a prime example being those related to the endoplasmic reticulum (ER). The pathological sequelae that arise from disruption of ER homeostasis are not well defined. The ER is an organelle that is responsible for secretory protein biosynthesis and the quality control of protein folding. The ER triggers an unfolded protein response (UPR) when misfolded proteins accumulate, and while the UPR acts to restore protein folding and ER homeostasis, this response can work as a switch to determine the death or survival of cells. The treatment of cancer with agents that target the UPR has shown promising outcomes. The UPR has wide crosstalk with other signaling pathways. Multi-targeted cancer therapies which target the intersections within signaling networks have shown synergistic tumoricidal effects. In the present review, the basic cellular and signaling pathways of the ER and UPR are introduced; then the crosstalk between the ER and other signaling pathways is summarized; and ultimately, the evidence that the UPR is a potential target for cancer therapy is discussed. Regulation of the UPR downstream signaling is a common therapeutic target for different tumor types. Tumoricidal effects achieved from modulating the UPR downstream signaling could be enhanced by phosphodiesterase 5 (PDE5) inhibitors. Largely untapped by Western medicine for cancer therapies are Chinese herbal medicines. This review explores and discusses the value of some Chinese herbal extracts as PDE5 inhibitors.
Formatted abstract
Endoplasmic reticulum (ER) stress is a phenomenon that occurs when excessive protein misfolding occurs during biosynthesis. ER stress triggers a series of signaling and transcriptional events known as the unfolded protein response (UPR). The UPR attempts to restore homeostasis in the ER but if unsuccessful can trigger apoptosis in the stressed cells and local inflammation. Intestinal secretory cells are susceptible to ER stress because they produce large amounts of complex proteins for secretion, most of which are involved in mucosal defense. This review focuses on ER stress in intestinal secretory cells and describes how increased protein misfolding could occur in these cells, the process of degradation of misfolded proteins, the major molecular elements of the UPR pathway, and links between the UPR and inflammation. Evidence is reviewed from mouse models and human inflammatory bowel diseases that ties ER stress and activation of the UPR with intestinal inflammation, and possible therapeutic approaches to ameliorate ER stress are discussed.
Copyright © 2010 the American Physiological Society.
Keyword Endoplasmic reticulum
Protein misfolding
Goblet cell
Paneth cell
Inflammatory bowel diseases
Endoplasmic-reticulum stress
Alpha-defensin expression
Ubiquitin ligase complex
Genome-wide association
Airway epithelial-cells
Ileal crohns-disease
MUC gene-expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2011 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 68 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 06 Jun 2010, 10:08:55 EST