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Cancer Discov. 2015 Jun;5(6):586-97. doi: 10.1158/2159-8290.CD-14-1490. Epub 2015 May 14.

Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis.

Author information

1
Oncogenesis, Stress, Cancer, University of Rennes, Rennes, France. Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France. eric.chevet@inserm.fr chetz@hsph.harvard.edu chetz@med.uhile.cl afshin.samali@nuigalway.ie.
2
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Santiago, Chile. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts. eric.chevet@inserm.fr chetz@hsph.harvard.edu chetz@med.uhile.cl afshin.samali@nuigalway.ie.
3
Apoptosis Research Centre, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland. eric.chevet@inserm.fr chetz@hsph.harvard.edu chetz@med.uhile.cl afshin.samali@nuigalway.ie.

Abstract

Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.

SIGNIFICANCE:

ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical efficacy with an acceptable safety profile.

PMID:
25977222
DOI:
10.1158/2159-8290.CD-14-1490
[Indexed for MEDLINE]
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