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Signaling the Unfolded Protein Response in cancer

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Endoplasmic Reticulum Stress in Health and Disease

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Abstract

Cancer cells present a deregulated replication cycle and are able to grow quickly in hostile environments. These cells can be subjected to many environmental challenges such as hypoxia, nutrient deprivation, remodeling of the environmental space or presence of chemotherapeutic agents. Moreover cancer cells also have to cope with elevated oxidative stress, high DNA replication and protein synthesis rates. As a consequence cancer cells must show high adaptive capabilities in order to cope with such stresses. In the past couple of years, the Unfolded Protein Response (UPR) has emerged as an important adaptive response for cancer cells to manage these stresses and to survive under challenging conditions. Although the UPR is primarily a pro-survival response, it can also induce cell death if the stress is not alleviated. In addition to presenting enhanced adaptive capacity, cancer cells have also developed strategies to get around UPR-induced death signals. In the present chapter, we describe how cancer cells use the UPR or have altered the UPR signaling machinery to gain selective advantage over surrounding cells. We also discuss how UPR signaling is connected to classical carcinogenic pathways. Finally, we will focus our attention in particular on IRE1 signaling pathways. Collectively these elements constitute an integrated adaptive system in cancer and therefore open the way to new potential anticancer therapeutic avenues.

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Abbreviations

ARE:

antioxidant responsive element

ATF4:

activating transcription factor-4

ATF6:

activating transcription factor-6

ASK1:

apoptosis signal-regulating kinase-1

BI1:

BAX inhibitor-1

BiP:

immunoglobulin heavy chain-binding protein

CHOP:

C/EBP-homologous protein

EDEM1:

ER degradation enhancing mannosidase-like protein-1

eIF2α:

alpha-subunit of the eukaryotic translation initiation factor-2

ER:

endoplasmic reticulum

ERAD:

ER-associated degradation

ERdj:

ER DNAJ like

Ero1:

ER oxidoreductin 1

ERSE:

ER stress-response element

GADD34:

growth arrest and DNA damage 34

GRP78:

78 kDa glucose-regulated protein

GRP94:

94 kDa glucose-regulated protein

IRE1:

inositol-requiring protein-1

IP3R1:

inositol 1,4,5-trisphosphate receptor 1

JNK:

c-Jun N-terminal kinase

Keap1:

Kelch-like ECH-associated protein-1

MAP:

mitogen-activated protein

MAPK:

MAP kinase

MAPKK:

MAP kinase kinase

MAPKKK:

MAP kinase kinase kinase

Nrf2:

nuclear factor-E2-related factor-2

PERK:

protein kinase RNA-like ER kinase

PI3 K:

phosphoinositide-3-kinase

PDI:

protein disulfide isomerase

RIDD:

regulated IRE1-dependent mRNA decay

ROS:

reactive oxygen species

sXBP1:

spliced form of XBP1

S1P and S2P:

site-1 and site-2 proteases

TNF:

tumor necrosis factor

TRAF2:

TNF receptor-associated factor-2

UPR:

unfolded protein response

XBP1:

X-box binding protein-1

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Authors and Affiliations

  1. Inserm U1053, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076, Bordeaux, France

    Stéphanie Lhomond & Eric Chevet

  2. GREF, Université Bordeaux Segalen, Bordeaux, France

    Stéphanie Lhomond & Eric Chevet

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  1. Stéphanie Lhomond
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  1. Dept Molec Cell Bio, K.U. Leuven, Harestraat/Gasthuisberg, B-3000 Leuven, 3000, Belgium

    Patrizia Agostinis

  2. School of Natural Science, Department of Biochemistry, NUI Galway, University Road, Galway, Ireland

    Samali Afshin

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Lhomond, S., Chevet, E. (2012). Signaling the Unfolded Protein Response in cancer. In: Agostinis, P., Afshin, S. (eds) Endoplasmic Reticulum Stress in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4351-9_16

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