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Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling

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Coordinating Organismal Physiology Through the Unfolded Protein Response

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 414))

Abstract

In the tumor microenvironment, cancer cells encounter both external and internal factors that can lead to the accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER) lumen, thus causing ER stress. When this happens, an adaptive mechanism named the Unfolded Protein Response (UPR) is triggered to help the cell cope with this change and restore protein homeostasis in the ER. Sequentially, one would expect that the activation of the three UPR branches, driven namely by IRE1, PERK, and ATF6, are crucial for the adaptation of cancer cells to the changing environment and thus for their survival and further propagation. Indeed, in the last few years, an increasing amount of studies has shown the implication of UPR signaling in different aspects of carcinogenesis and tumor progression. Features such as sustaining proliferation and resistance to cell death, genomic instability, altered metabolism, increased inflammation and tumor-immune infiltration, invasion and metastasis, and angiogenesis, defined as “the hallmarks of cancer”, can be regulated by the UPR machinery. At the same time, new potential therapeutic interventions applicable to different kinds of cancers are being revealed. In order to describe the emerging role of UPR in cancer biology, these are the points that will be discussed in this chapter.

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Abbreviations

ADAM17:

ADAM metallopeptidase domain 17

AKT:

Protein kinase B (PKB)

ALL:

Acute lymphoblastic leukemia

APC:

Antigen-presenting cells

APY29:

N2-1H-Benzimidazol-6-yl-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-2,4-pyrimidinediamine

ASK1:

Apoptosis signal-regulating kinase 1

ATF3:

Activating transcription factor 3

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

ATF6f:

ATF6 cytoplasmic domain

ATG5:

Autophagy protein 5

ATM:

Ataxia-telangiectasia mutated (Ser/Thr protein kinase)

BCR:

Breakpoint cluster region

BiP:

Binding immunoglobin protein or GRP78

CAC:

Colitis-associated cancer

CAF:

Cancer-associated fibroblasts

CCL2:

Chemokine (C-C motif) ligand 2 or MCP-1

CD8/28/40/80/86:

Cluster of differentiation 8/28/40/80/86

CHOP:

C/EBP-homologous protein

CNS:

Central nervous system

CreP:

Protein phosphatase 1 regulatory subunit 15B (PPP1R15B)

CRT:

Calreticulin

CXCL3/8/10/14:

C-X-C motif chemokine ligand 3/8/10/14

DC:

Dendritic cells

E2F:

Family of transcription factors (TF) in higher eukaryotes

EC:

Endothelial cells

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EGR-1:

Early growth response protein 1

eIF2B:

Guanine nucleotide exchange factor for the eukaryotic initiation factor 2

eIF2α:

Eukaryotic initiation factor 2α

EMT:

Epithelial-to-mesenchymal transition

EPR:

Epiregulin

ER:

Endoplasmic reticulum

ER+:

Estrogen receptor positive

ErbB1:

Synonym of EGFR

ERO1α:

Endoplasmic reticulum oxidoreductase 1 alpha

FAK:

Focal adhesion kinase

FGF:

Fibroblast growth factor

FGF2:

Fibroblast growth factor 2

FOXO:

Forkhead box O

FOXP3:

Forkhead box P3

GADD34:

Growth arrest and DNA damage-inducible protein GADD34/Protein phosphatase 1 regulatory subunit 15A (PP1R15A)

GBM:

Glioblastoma multiforme

GLUT1:

Glucose transporter 1

gp96/GRP94:

Glycoprotein 96/94 kDa glucose-regulated protein

GRP78:

78 kDa glucose-regulated protein

HDAC:

Histone deacetylase

HIF1α:

Hypoxia-inducible factor 1-alpha

IL1/1β/2/6/8/10/17/23:

Interleukin 1/1β/2/6/8/10/17/23

IRE1α:

Endoribonuclease inositol-requiring enzyme 1 alpha

ISC:

Intestinal stem cells

ISRIB:

Integrated stress response inhibitor

JNK:

c-Jun N-terminal kinase

Keap1:

Kelch-like ECH-associated protein 1

KIRA:

Kinase-inhibiting RNase attenuators

LAMP3:

Lysosomal-associated membrane protein 3

LC3B:

Microtubule-associated proteins 1A/1B-light chain 3B

MAF:

MAF BZIP Transcription Factor

MAFB:

MAF BZIP transcription factor B

MCP-1:

Monocyte chemoattractant protein-1 or CCL2

MDSC:

Myeloid-derived suppressor cells

MHC I/II:

Major histocompatibility complex I/II

MIP-1α/MIP-1β:

Macrophage inflammatory protein-1α/β

miRNA:

Micro RNA

MMP:

Matrix metalloproteinase

mRNA:

Messenger RNA

mTOR:

Mechanistic target of rapamycin

mTORC1:

Mammalian target of rapamycin complex 1

ΜΦ:

Macrophages

NFκB p65/RelA:

Nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit

NRF2:

Nuclear factor (erythroid-derived 2)-like 2

p53:

Tumor protein p53

p97/VCP:

Valosin-containing protein

PDI:

Protein disulfide isomerase

PDIA5:

Protein disulfide isomerase family A member 5

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

PLCγ:

Phospholipase C gamma

PP1c:

Protein phosphatase 1 catalytic subunit

PTM:

Post-translational modification

RhoA:

Ras homolog gene family, member A

ROS:

Reactive oxygen species

rRNA:

Ribosomal RNA

RtcB:

TRNA-splicing ligase RtcB homolog/C22orf28/HSPC117

RUVBL2:

RuvB-like 2

S1P:

Site-1 protease

S1PR1:

Sphingosine-1-phosphate receptor 1

S2P:

Site-2 protease

SCCA1:

Squamous cell carcinoma antigen 1

SNAIL:

Zinc finger protein SNAI1

SPARC:

Secreted protein acidic and rich in cysteine

SRC:

Tyrosine-protein kinase Src

STAT3/6:

Signal transducer and activator of transcription-3/-6

TAC:

Transit-amplifying cells

TAM:

Tumor-associated macrophages

TDAG51:

T-cell death-associated gene 51 protein

Tg:

Thapsigargin

TGF-β:

Transforming growth factor beta

TGF-β1:

Transforming growth factor beta 1

THBS1:

Thrombospondin 1

TNBC:

Triple negative breast cancer

TNFα:

Tumor necrosis factor alpha

TRAF2:

TNF receptor-associated factor 2

Tun:

Tunicamycin

Twist:

Twist-related protein 1 (TWIST1)

UPR:

Unfolded protein response

VEGF-A:

Vascular endothelial growth factor A

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

WNT:

Wingless-related integration site

WNT11:

WNT family member 11

XBP1:

X-box binding protein 1

XBP1s:

Spliced form (active) of X-box binding protein 1

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Acknowledgements

This work was funded by grants from the Institut National du Cancer (INCa) and EU H2020 MSCA ITN-675448 (TRAINERS) to EC.

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Authors and Affiliations

  1. Inserm U1242 «Chemistry, Oncogenesis, Stress and Signaling», University of Rennes 1, Rennes, France

    Alexandra Papaioannou & Eric Chevet

  2. Centre de Lutte contre le Cancer Eugène Marquis, Avenue de la bataille Flandres Dunkerque, 35000, Rennes, France

    Alexandra Papaioannou

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  1. Alexandra Papaioannou
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Correspondence to Eric Chevet .

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  1. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA

    R. Luke Wiseman

  2. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Cole M. Haynes

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Papaioannou, A., Chevet, E. (2017). Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling. In: Wiseman, R., Haynes, C. (eds) Coordinating Organismal Physiology Through the Unfolded Protein Response. Current Topics in Microbiology and Immunology, vol 414. Springer, Cham. https://doi.org/10.1007/82_2017_36

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