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The impact of the endoplasmic reticulum protein-folding environment on cancer development

Key Points

  • Defective protein folding in the endoplasmic reticulum (ER) and unfolded protein response (UPR) activation are documented in many human cancer types, which is attributed to both intrinsic and extrinsic factors.

  • UPR activation is a vital step for oncogenic transformation, as UPR signalling molecules interact with well-established oncogene and tumour suppressor gene networks to modulate their function during cancer development.

  • Conditions of low nutrient supply (for example, glucose or oxygen deprivation), as well as excess nutrients (fatty acids, cholesterol and glucose) induce ER stress and UPR activation. UPR induction promotes cancer cell survival through induction of autophagy and adaptation to the stressful microenvironment.

  • ER stress and UPR activation possibly promote cancer development and progression through modulating inflammatory responses.

  • The UPR is indispensable in cells in the tumour microenvironment to either promote or inhibit cancer progression.

  • Targeting the UPR, through single or combination therapy, provides a promising therapeutic approach for many different cancers.

Abstract

The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells for the storage and regulated release of calcium and as the entrance to the secretory pathway. Protein misfolding in the ER causes accumulation of misfolded proteins (ER stress) and activation of the unfolded protein response (UPR), which has evolved to maintain a productive ER protein-folding environment. Both ER stress and UPR activation are documented in many different human cancers. In this Review, we summarize the impact of ER stress and UPR activation on every aspect of cancer and discuss outstanding questions for which answers will pave the way for therapeutics.

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Figure 1: The unfolded protein response (UPR) signalling pathways.
Figure 2: Crosstalk between the unfolded protein response (UPR) components and oncogene or tumour suppressor gene networks in cancer cells.
Figure 3: The unfolded protein response (UPR) and inflammation.
Figure 4: The cancer-supporting role of the unfolded protein response (UPR).

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Acknowledgements

The authors apologize to those whose work could not be cited owing to length restraints. R.J.K. is supported by US National Institutes of Health (NIH) grants DK042394, DK088227 and HL052173.

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Glossary

ER-associated degradation

(ERAD). A process by which misfolded proteins in the endoplasmic reticulum (ER) are targeted by retrotranslocation and ubiquitylation for subsequent degradation by the proteasome.

Mitochondria-associated ER membranes

(MAMs). A specialized endoplasmic reticulum (ER) membrane is directly juxtaposed to the mitochondrion to coordinate efficient communication between these two organelles.

Polysome

A cluster of ribosomes translating a single mRNA molecule.

Regulated IRE1-dependent decay

(RIDD). A process in which activated inositol-requiring protein 1 (IRE1) induces cleavage and degradation of microRNAs and of mRNAs encoding membrane and secreted proteins.

Regulated intramembrane proteolysis

A process in which endoplasmic reticulum (ER) transmembrane transcription factors are cleaved within the plane of the membrane to release cytosolic fragments that enter the nucleus to regulate gene transcription.

Inflammasome

A large intracellular multiprotein oligomeric complex that is activated by pattern recognition receptors to initiate an innate immune response by maturation of the inflammatory cytokines interleukin-1 (IL-1) and IL-18.

Type M2 macrophage

A subset of activated macrophages that are involved in immunosuppression and tissue repair.

MHC class I pathway

(Major histocompatability complex class I pathway). A pathway by which cells present peptides from cytosolic proteins to T cells.

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Wang, M., Kaufman, R. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer 14, 581–597 (2014). https://doi.org/10.1038/nrc3800

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