Review
Targeting the endoplasmic reticulum-stress response as an anticancer strategy

https://doi.org/10.1016/j.ejphar.2009.06.064Get rights and content

Abstract

The endoplasmic reticulum (ER) is the site of synthesis and folding of secretory and membrane bound proteins. The capacity of the ER to process proteins is limited and the accumulation of unfolded and misfolded proteins can lead to ER stress which has been associated with a wide range of diseases including cancer. In this review we initially provide an overview of our current understanding of how cells respond to ER stress at the molecular level and the key players involved in mediating the unfolded protein response (UPR). We review the evidence suggesting that the ER stress response could be important for the growth and development of tumors under stressful growth conditions such as hypoxia or glucose deprivation, which are commonly encountered by most solid tumors, and we analyse how it may be possible to exploit the unfolded protein response as an anticancer strategy. Two approaches to target the unfolded protein response are proposed—the first involves inhibiting components of the unfolded protein response so cells cannot adapt to stressful conditions and the second involves overloading the unfolded protein response so the cell is unable to cope, leading to cell death. We focused on proteins with an enzymatic activity that can be targeted by small molecule inhibitors as this is one of the most common approaches utilized by drug discovery companies. Finally, we review drugs currently in clinical development that affect the ER stress response and that may have potential as anti-tumor agents alone or in combination with other chemotherapeutics.

Section snippets

Endoplasmic reticulum stress and the unfolded protein response: an overview

The endoplasmic reticulum (ER) comprises a complex membranous network found in all eukaryotic cells. It plays a crucial role in normal cellular functioning, particularly with regard to folding and post-translational modification of secretory proteins and membrane proteins, that are synthesized along the membrane of the rough ER and passed onto the Golgi apparatus for post-translational modifications, such as glycosylation and lipidation. In order to accomplish its protein folding functions the

Therapeutic targeting of ER stress pathways: an overview

The cellular response to ER stress is currently understood to elicit partially overlapping and conflicting signals. On the one hand it induces cytoprotective functions by activating signaling pathways to reestablish cellular homeostasis, while on the other hand, if the stress is prolonged and unresolved, then signaling pathways that promote apoptosis are activated. The current hypothesis is that the protective functions provide a window for the cell to resolve the stress and reestablish

State of the art: drugs currently in development affecting ER stress pathways

There are a number of drugs under development that affect one or more of the branches of the unfolded protein response (Table 2), although a drug discovery effort aimed at specifically inhibiting the unfolded protein response is, to our knowledge still lacking. However, there are a few grant applications that have been funded to investigate this approach (http://www.cancerportfolio.org). Below we have outlined different compounds that affect the unfolded protein response although it may not be

Future perspectives and remaining questions

Due to the demands made on cells by the malignant process, the induction of the ER stress pathway is likely to be an important contributor to tumor survival and growth, and an activated stress response may also be a key driver in the development of resistance to chemotherapeutic agents. One of the major challenges for cancer therapy is finding a therapeutic window where it is possible to selectively kill cancer cells without harming normal cells. The activation of the unfolded protein response

Acknowledgements

Our work on ER stress is supported by grants from Science Foundation Ireland (05/IN3/B851) and Enterprise Ireland.

References (114)

  • K. Maundrell et al.

    Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1

    J. Biol. Chem.

    (1997)
  • E.A. Obeng et al.

    Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells

    Blood

    (2006)
  • H.O. Pae et al.

    Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells

    Biochem. Biophys. Res. Commun.

    (2007)
  • H. Puthalakath et al.

    ER stress triggers apoptosis by activating BH3-only protein Bim

    Cell

    (2007)
  • R.K. Reddy et al.

    The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis

    J. Biol. Chem.

    (1999)
  • R.K. Reddy et al.

    Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation

    J. Biol. Chem.

    (2003)
  • S. Reuter et al.

    Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells

    Biochem. Pharmacol.

    (2008)
  • D.T. Rutkowski et al.

    A trip to the ER: coping with stress

    Trends Cell Biol.

    (2004)
  • F.T. Salles et al.

    Brefeldin-A induces apoptosis in human adenoid cystic carcinoma cultured cells

    Oral Oncol.

    (2004)
  • A. Samali et al.

    Heat shock proteins increase resistance to apoptosis

    Exp. Cell Res.

    (1996)
  • Z.M. Shao et al.

    The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis

    Exp. Cell Res.

    (1998)
  • T. Suzuki et al.

    Reduction of GRP78 expression with siRNA activates unfolded protein response leading to apoptosis in HeLa cells

    Arch. Biochem. Biophys.

    (2007)
  • H. Uramoto et al.

    Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance

    Lung Cancer

    (2005)
  • E. Wallen et al.

    Brefeldin A induces p53-independent apoptosis in primary cultures of human prostatic cancer cells

    J. Urol.

    (2000)
  • Q. Wang et al.

    Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance

    Cancer Detect. Prev.

    (2005)
  • J.A. Aguirre-Ghiso et al.

    Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth

    Cancer Res.

    (2004)
  • J. Bakhshi et al.

    Coupling endoplasmic reticulum stress to the cell death program in mouse melanoma cells: effect of curcumin

    Apoptosis

    (2008)
  • A. Banerjea et al.

    Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity

    Mol. Cancer

    (2004)
  • M. Bi et al.

    ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth

    EMBO J.

    (2005)
  • J.D. Blais et al.

    Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress

    Mol. Cell. Biol.

    (2006)
  • P. Boya et al.

    Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization

    Cell Death Differ.

    (2002)
  • M. Boyce et al.

    Cellular response to endoplasmic reticulum stress: a matter of life or death

    Cell Death Differ.

    (2006)
  • J.W. Brewer et al.

    Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • J.S. Carew et al.

    Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine

    Leukemia

    (2004)
  • M.E. Cheetham et al.

    Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function

    Cell Stress Chaperones

    (1998)
  • M. Corazzari et al.

    Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57

    Br. J. Cancer

    (2007)
  • S.B. Cullinan et al.

    Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival

    Mol. Cell. Biol.

    (2003)
  • D.J. Davidson et al.

    Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78

    Cancer Res.

    (2005)
  • W.G. Deng et al.

    Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts

    FASEB J.

    (2001)
  • S.R. Denmeade et al.

    The SERCA pump as a therapeutic target: making a “smart bomb” for prostate cancer

    Cancer Biol. Ther.

    (2005)
  • D. Dong et al.

    Spontaneous and controllable activation of suicide gene expression driven by the stress-inducible grp78 promoter resulting in eradication of sizable human tumors

    Hum. Gene Ther.

    (2004)
  • D. Dong et al.

    Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development

    Cancer Res.

    (2008)
  • O. Donze et al.

    The protein kinase PKR: a molecular clock that sequentially activates survival and death programs

    EMBO J.

    (2004)
  • B. Drogat et al.

    IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo

    Cancer Res.

    (2007)
  • S.P. Ermakova et al.

    (−)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78

    Cancer Res.

    (2006)
  • D.E. Feldman et al.

    The unfolded protein response: a novel component of the hypoxic stress response in tumors

    Mol. Cancer Res.

    (2005)
  • D.R. Fels et al.

    Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways

    Cancer Res.

    (2008)
  • P.M. Fernandez et al.

    Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions

    Breast Cancer Res. Treat.

    (2000)
  • A. Fribley et al.

    Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells

    Mol. Cell. Biol.

    (2004)
  • Cited by (265)

    View all citing articles on Scopus
    View full text