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The role of the unfolded protein response in tumour development: friend or foe?

Nature Reviews Cancer volume 4, pages 966–977 (2004)Cite this article

Key Points

  • When eukaryotic cells encounter adverse physiological conditions that impact on protein folding in the endoplasmic reticulum, a signal-transduction cascade is activated; this is termed the unfolded protein response (UPR).

  • The UPR is a multipronged response that is largely cytoprotective, but under conditions of prolonged stress apoptotic components are activated.

  • The UPR can be activated in tumours; this is apparently due to their inadequate vascularization. This results in limited oxygen and nutrients, which impinge on the normal maturation of secretory-pathway proteins.

  • Activation of the UPR might promote dormancy, aid tumour growth or protect the host by inducing apoptosis. It is presently unclear where the balance lies and how the fate of a tumour cell is eventually decided, although the part of the UPR pathway that upregulates endoplasmic reticulum chaperones seems to have a protective role during tumour development.

  • In vitro activation of the UPR alters the sensitivity of tumour cells to chemotherapeutic agents.

  • Although several interesting observations have been made to implicate the UPR in tumour growth and resistance to treatments, more comprehensive in vivo studies need to be done to determine how large of a role it has and to identify the most important components of the pathway, and to determine which stages of tumour development are regulated by the UPR.

Abstract

Having accumulated mutations that overcome cell-cycle and apoptotic checkpoints, the main obstacle to survival faced by a cancer cell is the restricted supply of nutrients and oxygen. These conditions impinge on protein folding in the endoplasmic reticulum and activate a largely cytoprotective signalling pathway called the unfolded protein response. Prolonged activation of this response can, however, terminate in apoptosis. Recent delineation of the components of this response, coupled with several clinical studies, indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.

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Figure 1: Schematic of endoplasmic reticulum functions under non-stress conditions.
Figure 2: Downstream elements of the unfolded protein response and potential stages of tumour development where it might contribute or interfere.
Figure 3: The pro- and anti-apoptotic roles of the unfolded protein response pathway in normal and malignant cells.
Figure 4: Aspects of the mammalian unfolded protein response that might cause increased resistance to topoisomeras-II-targeting drugs like etoposide (blue and grey) or increased sensitivity to DNA-crosslinking agents like cisplatin (green).

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Acknowledgements

The authors wish to thank I. Boime and J. Aguirre-Ghiso for helpful comments.

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Authors and Affiliations

  1. Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Yanjun Ma & Linda M. Hendershot

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  1. Yanjun Ma
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  2. Linda M. Hendershot
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Correspondence to Linda M. Hendershot.

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DATABASES

Entrez Gene

APAF1

ATF4

BAD

BAK

BAX

BCL2

BiP

caspase-3

caspase-7

caspase-9

GADD34

GCN2

GRP94

GRP170

GSK3β

Hac1

HIF1α

Ire1

JAB1

p38

p53

PAI1

PERK

Rlg1

topoisomerase IIα

uPA

VEGF

Glossary

ENDOPLASMIC RETICULUM

A key organelle in all eukaryotic cells and the site of synthesis, folding, assembly and quality control of proteins that are to become part of the cell membrane (for example, transmembrane receptors and other integral membrane proteins) as well as proteins that are to be secreted or 'exocytosed' from the cell (for example, digestive enzymes).

MOLECULAR CHAPERONES

A family of cellular proteins that mediate the correct assembly or disassembly of nascent polypeptides and, in some cases, their assembly into oligomeric structures, but which are not components of those final structures. They probably assist assembly by preventing inappropriate interactions during folding that would result in non-functional structures.

PROTEASOME

A 26S multiprotein complex that catalyses the breakdown of polyubiquitylated proteins.

Ire1

An endoplasmic reticulum (ER) transmembrane protein that contains three main functional domains: the ER luminal stress-sensing domain; a cytosolic kinase domain that is activated when Ire1 dimerizes and phosphorylates in trans; and a cytosolic endonuclease domain that cleaves Hac1 mRNA in yeast or XBP1 mRNA in higher organisms.

CONFORMATIONAL DISEASES

A group of heterologous disorders in which a host protein is mutated or undergoes a change in conformation that interferes with its proper maturation and results in its accumulation in the ER. The most prominent examples are Alzheimer's, Parkinson's and Creutzfeldt–Jakob diseases.

XBP1

A transcription factor, the mRNA of which is a substrate of the endonuclease activity of Ire1. Under non-stressed conditions, XBP1 protein levels are very low. During endoplasmic reticulum stress, 26 bases are excised from the XBP1 mRNA by Ire1, resulting in a frameshift. The new reading frame encodes a stronger transactivation domain. The transcription of XBP1 is also increased during ER stress because of the transactivation of its promoter by ATF6.

ATF6

An endoplasmic reticulum (ER) transmembrane protein that contains an ER luminal stress-sensing domain and a cytosolic domain that encodes a transcription factor. During ER stress, BiP dissociates from the luminal domain of ATF6 and allows it to traffick to the Golgi, where it is cleaved by two proteases, S1P and S2P. The cytosolic transcription-factor domain is released and migrates to the nucleus, where it transactivates downstream promoters.

CHOP

A transcription factor that is homologous to C/EBP. It homodimerizes to activate specific downstream targets, heterodimerizes with C/EBP family members to alter their transactivation activity, or heterodimerizes with non-C/EBP family members to activate brand new targets. CHOP has been implicated in the apoptotic event occurring during ER stress.

PERK

An endoplasmic reticulum (ER) transmembrane protein that contains an ER luminal stress-sensing domain and a cytosolic kinase domain that, on activation, phosphorylates eIF-2α, resulting in general protein synthesis inhibition.

eIF-2α

The smallest subunit of eIF-2, which recruits Met-tRNAi to the mRNA–40S ribosome complex when bound to GTP. Phosphorylation of this subunit during stress inhibits the assembly of the eIF-2 initiation complex, thereby blocking general protein synthesis. The phosphorylation state of eIF-2α is regulated by a family of kinases including PERK, PKR, GCN2 and HRI.

CASPASE-12

Caspase-12 belongs to the group I family of caspases or ICE-like caspases, which contain a long pro-domain responsible for interaction with various adaptor proteins (CARD domain) and two catalytic subunits: p20 and p10. The activation of caspase-12 seems to be restricted to the UPR and is not activated during apoptosis induced by serum deprivation, tumour-necrosis factor, cyclohexamide or anti-FAS treatment.

POSITRON-EMISSION TOMOGRAPHY

Tomographic imaging technique that detects nuclides as they decay by positron emission. The emitted positrons collide with a free electron, resulting in the conversion of matter to two γ-rays, which emerge in opposite directions.

DORMANCY

Dormancy refers to cancer cells that have exited cell cycle and do not grow for prolonged periods of time in the host, but which remain viable and can be activated to re-enter the cell cycle if the appropriate growth signals are received. In experiments, tumours deprived of angiogenesis remained dormant, whereas the acquisition of a blood supply led to rapid logarithmic growth.

MITOGEN-ACTIVATED PROTEIN KINASES

A group of serine/threonine kinases that mediate the response of cells to many extracellular stimuli, such as cytokines and growth factors. These protein kinases include the extracellular signal-regulated protein kinases and two stress-activated protein kinases, the c-JUN N-terminal kinases and the p38 mitogen-activated protein kinase. Activation of these kinases can lead to proliferative or apoptotic signalling.

REACTIVE OXYGEN SPECIES

Highly reactive chemical radicals that are generated as products of oxygen degradation.

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Ma, Y., Hendershot, L. The role of the unfolded protein response in tumour development: friend or foe?. Nat Rev Cancer 4, 966–977 (2004). https://doi.org/10.1038/nrc1505

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