ER stress and cancer: the FOXO forkhead transcription factor link

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Title: ER stress and cancer: the FOXO forkhead transcription factor link
Authors: Alasiri, G
Fan, LY
Zona, S
Goldsbrough, IG
Ke, HL
Auner, HW
Lam, EW
Item Type: Journal Article
Abstract: The endoplasmic reticulum (ER) is a cellular organelle with central roles in maintaining proteostasis due to its involvement in protein synthesis, folding, quality control, distribution and degradation. The accumulation of misfolded proteins in the ER lumen causes ‘ER stress’ and threatens overall cellular proteostasis. To restore ER homeostasis, cells evoke an evolutionarily conserved adaptive signalling and gene expression network collectively called the ‘unfolded protein response (UPR)’, a complex biological process which aims to restore proteostasis. When ER stress is overwhelming and beyond rectification, the normally pro-survival UPR can shift to induce cell termination. Emerging evidence from mammalian, fly and nematode worm systems reveals that the FOXO Forkhead proteins integrate upstream ER stress and UPR signals with the transcriptional machinery to decrease translation, promote cell survival/termination and increase the levels of ER-resident chaperones and of ER-associated degradation (ERAD) components to restore ER homeostasis. The high rates of protein synthesis/translation associated with cancer cell proliferation and metabolism, as well as mutations resulting in aberrant proteins, also induce ER stress and the UPR. While the pro-survival side of the UPR underlies its ability to sustain and promote cancers, its apoptotic functions can be exploited for cancer therapies by offering the chance to ‘flick the proteostatic switch’. To this end, further studies are required to fully reevaluate the roles and regulation of these UPR signalling molecules, including FOXO proteins and their targets, in cancer initiation and progression as well as the effects on inhibiting their functions in cancer cells. This information will help to establish these UPR signalling molecules as possible therapeutic targets and putative biomarkers in cancers.
Issue Date: 29-May-2017
Date of Acceptance: 24-May-2017
ISSN: 1872-8057
Publisher: Elsevier
Start Page: 67
End Page: 81
Journal / Book Title: Molecular and Cellular Endocrinology
Volume: 462
Issue: Part B
Copyright Statement: © 2017 Elsevier B.V. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Royal Embassy Of Saudi Arabia
Royal Embassy Of Saudi Arabia
Funder's Grant Number: C37/A12011
Keywords: Cancer
ER stress
Endoplasmic reticulum
Forkhead transcription factors
Unfolded protein response
06 Biological Sciences
11 Medical And Health Sciences
07 Agricultural And Veterinary Sciences
Endocrinology & Metabolism
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine

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