Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jun;19(2):75-88.
doi: 10.15430/JCP.2014.19.2.75.

Endoplasmic reticulum stress and cancer

Raj Kumar Yadav  1 , Soo-Wan Chae  1 , Hyung-Ryong Kim  2 , Han Jung Chae  1
Affiliations
Review

Endoplasmic reticulum stress and cancer

Raj Kumar Yadav et al. J Cancer Prev. 2014 Jun.

Abstract

The endoplasmic reticulum (ER) is the principal organelle responsible for multiple cellular functions including protein folding and maturation and the maintenance of cellular homeostasis. ER stress is activated by a variety of factors and triggers the unfolded protein response (UPR), which restores homeostasis or activates cell death. Multiple studies have clarified the link between ER stress and cancer, and particularly the involvement of the UPR. The UPR seems to adjust the paradoxical microenvironment of cancer and, as such, is one of resistance mechanisms against cancer therapy. This review describes the activity of different UPRs involved in tumorigenesis and resistance to cancer therapy.

Keywords: Cancer; Endoplasmic reticulum stress; Unfolded protein response.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
During endoplasmic reticulum (ER) stress, glucose regulated protein 78 binds to misfolded proteins, activating inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6) and pancreatic ER kinase-like ER kinase (PERK). PERK is activated by dimerization and autophosphorylation and phosphorylates eukaryotic initiation factor 2α (elF2α). Phosphorylated elf2α inhibits protein synthesis and activates the transcription of ATF4, inducing the transcription of downstream genes. IRE1α produces a spliced form of XBP1 (XBP1s) due to its RNase activity. IRE1 assists protein folding and degradation. ATF6 translocates from the ER to the Golgi apparatus, where it is cleaved by protease activity, forming active nuclear ATF6 (N). CHOP, CCAAT/enhancer binding protein homologous protein, ERAD, ER-associated protein degradation.
Figure 2.
Figure 2.
Cancer cells grow continuously, develop decreased nutrition supplies and increase reactive oxygen species (ROS) production, thereby inducing hypoxia and activating endoplasmic reticulum (ER) stress. ER stress activates the unfolded protein response (UPR). The UPR is both apoptotic and adaptive in tumor cells. The adaptive activity of UPR induces anti-apoptotic NF-κB, which inhibits p53 dependent apoptotic signals and induces angiogenic activity through increased vascular endothelial growth factor (VEGF) secretion. Mitogen-activated protein kinase (p38 MAPK) contributes to tumor cell dormancy during drug treatment through pancreatic ER kinase-like ER kinase (PERK)-eukaryotic initiation factor 2α, which arrests the growth of cells at G0/G1. Tumor-associated macrophages also secrete inflammatory cytokines that promote tumor growth, angiogenesis, invasion and metastasis during periods of ER stress. IRE1α, inositol-requiring enzyme 1α; ATF6, activating transcription factor 6.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13:184–90. - PMC - PubMed
    1. Rao RV, Niazi K, Mollahan P, Mao X, Crippen D, Poksay KS, et al. Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23. Cell Death Differ. 2006;13:415–25. - PMC - PubMed
    1. Martinon F. Targeting endoplasmic reticulum signaling pathways in cancer. Acta Oncol. 2012;51:822–30. - PubMed
    1. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000;101:249–58. - PubMed
    1. Tsai YC, Weissman AM. The Unfolded Protein Response, Degradation from Endoplasmic Reticulum and Cancer. Genes Cancer. 2010;1:764–78. - PMC - PubMed