Skip to main content
SpringerLink
Log in
Book cover

Endoplasmic Reticulum Stress in Health and Disease pp 383–412Cite as

UPR Activation in Cancer Cells: A Double-Edged Sword

  • Chapter
  • First Online:

  • 1537 Accesses

Abstract

Due to their rapid growth, tumors are frequently exposed to extracellular environments that are deficient in nutrients, low in oxygen and with sub-optimal pH. One result of this is the disruption of homeostasis in the Endoplasmic Reticulum (ER), which leads to the activation of a largely cytoprotective signaling pathway known as the unfolded protein response (UPR). Here we discuss three newly characterized aspects of UPR signaling and the effect they have on normal physiology as well as in tumor growth and survival. Included in this discussion is the UPR’s contribution to angiogenesis and the mechanisms tumors can use to appropriate this process to fuel their own growth; the identification of P-glycoprotein, a member of the ABC family of transporters, as a transcriptional target of the UPR and its possible link to the decreased sensitivity of tumor cells to chemotherapeutic drugs; and finally, the UPR’s ability to decrease translation via mTOR signaling and the mechanisms that tumor cells may use to elude this translational block of critical proteins to continue their growth.

E. R. Pereira and A. M. Preston contributed equally to this work.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

4EBP1:

4E-BP, isoforms 1-4

ABC:

ATP-Binding Cassette transporter

Abcb1:

ATP-binding cassette, sub-family B (MDR/TAP), member 1

ABL:

V-abl Abelson murine Leukemia viral oncogene

AKT:

Protein Kinase B

AMPK:

AMP-activated Protein Kinase

ARE:

Adeylate Rich Region

ATF4/6:

Activating Transcription Factor 4/6

ATM:

Ataxia Telangiectasia Mutated

AMP:

Adenosine Monophosphate

ATP:

Adenosine Triphosphate

Bcl-2:

B-cell lymphoma 2

BiP:

Immunoglobulin heavy chain-Binding Protein

CAM:

Chick chorio-Allantoic Membrane assay

deptor:

DEP domain TOR binding protein

eIF2α:

eukaryotic Initiation Factor-2α

eIF4F:

eukaryotic translation Initiation Factor 4F

ER:

Endoplasmic Reticulum

FGF2:

Fibroblast Growth Factor

GADD34:

Growth Arrest and DNA Damage protein 34

GDP:

Guanosine diphosphate

GTP:

Guanosine triphosphate

HIF:

Hypoxia-induced Factor

HRE:

Hypoxia-Responsive Element

IGF1R:

Insuline-like Growth Factor 1 Receptor

IL6/8:

Interleukin 6/8

IκB:

NF-κB inhibitor

IRE1:

Inositol Requiring Enzyme 1

IRS-1:

insulin receptor substrate 1

ISR:

Integrated Stress Response

JAB1:

Jun activation domain-binding protein-1

JNK:

Jun NH3-terminal kinase

MDR1:

multiple drug resistance gene 1

MEF:

Mouse Embryonic Fibroblast

mLST8:

mammalian lethal with SEC13 protein 8

MMP9:

Matrix MetalloPeptidase 9

mTOR:

mammalian Target of Rapamycin

mTORC:

mammalian Target of Rapamycin Complex

NF-κB:

Nuclear Factor of κ light polypeptide gene enhancer in B-cells

ORF:

Open Reading Frame

p38-MAPK:

p38- Mitogen Activated Protein Kinase

PDGFR:

Platelet-Derived Growth Factor Receptor

PERK:

double stranded RNA-activated protein kinase (PKR) –like ER Kinase

PH:

Pleckstrin Homology domain proteins

PI3K:

Phosphatidylinositol 3-Kinase

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol 3,4,5-trisphosphate

P-gp:

Poly-glycoprotein

PP1:

Protein Phosphatase 1

PRAS40:

Proline-Rich Akt Substrate 40

protor:

Protein binding rictor

raptor:

Regulatory associated protein of mTOR

Redd1:

Regulated in development and DNA damage responses 1

Rheb:

Ras homologue enriched in brain

rictor:

Rapamycin insensitive companion of mTOR

S6K1:

S6K isophorms 1-6

Sin1:

stress-activated protein kinase-interacting protein 1

SPARC:

Secreted Protein Acidic and Rich in Cysteine

TNFα:

Tumour Necrosis Factor alpha

topo IIα:

Topoisomerase IIα

TSC1/2:

Tuberous Sclerosis 2

UPR:

Unfolded Protein Response

VASH1:

Vasohibin

VCIP:

VEGF and type I Collagen Inducible Protein

VEGF:

Vascular Endothelial Growth Factor

VEGFA:

Vascular Endothelial Growth Factor

XBP1:

X-box Binding Protein 1

References

  1. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature reviews. Mol cell bio 8:519–529

    CAS  Google Scholar 

  2. Lee AS (1992) Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 4:267–273

    Article  PubMed  CAS  Google Scholar 

  3. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH (2003) Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4:321–329

    Article  PubMed  CAS  Google Scholar 

  4. Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol cell 7:1165–1176

    Article  PubMed  CAS  Google Scholar 

  5. Isler JA, Skalet AH, Alwine JC (2005) Human cytomegalovirus infection activates and regulates the unfolded protein response. J Virol 79:6890–6899

    Article  PubMed  CAS  Google Scholar 

  6. Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nature reviews. Mol Cell Biol 8:464–478

    CAS  Google Scholar 

  7. Salminen A, Kauppinen A, Hyttinen JM, Toropainen E, Kaarniranta K (2010) Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16:535–542

    Article  PubMed  CAS  Google Scholar 

  8. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  9. Ware JA, Simons M (1997) Angiogenesis in ischemic heart disease. Nat Med 3:158–164

    Article  PubMed  CAS  Google Scholar 

  10. Pereira ER, Liao N, Neale GA, Hendershot LM (2010) Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response. PloS One 5(9):e12521

    Article  PubMed  CAS  Google Scholar 

  11. Auf G, Jabouille A, Guerit S, Pineau R, Delugin M, Bouchecareilh M, Magnin N, Favereaux A, Maitre M, Gaiser T, von Deimling A, Czabanka M, Vajkoczy P, Chevet E, Bikfalvi A, Moenner M (2010) Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proceedings of the national academy of sciences of the United States of America 107:15553–15558

    Article  PubMed  CAS  Google Scholar 

  12. Iwawaki T, Akai R, Kohno K, Miura M (2004) A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat Med 10:98–102

    Article  PubMed  CAS  Google Scholar 

  13. Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ (2005) The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Investig 115:268–281

    PubMed  CAS  Google Scholar 

  14. Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proceedings of the national academy of sciences of the United States of America 106:16657–16662

    Google Scholar 

  15. Guzel E, Basar M, Ocak N, Arici A, Kayisli UA (2011) Bidirectional interaction between unfolded-protein-response key protein HSPA5 and estrogen signaling in human endometrium. Biol Reprod 85:121–127

    Article  PubMed  CAS  Google Scholar 

  16. Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. The journal of investigative dermatology. Symposium proceedings/the Society for Investigative Dermatology, Inc. (and) Eur Soc Dermatol Res 5:40–46

    Google Scholar 

  17. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611

    Article  PubMed  CAS  Google Scholar 

  18. Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

  19. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713

    Article  PubMed  CAS  Google Scholar 

  20. Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, Urano F (2010) Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PloS One 5:e9575

    Article  PubMed  CAS  Google Scholar 

  21. Oskolkova OV, Afonyushkin T, Leitner A, von Schlieffen E, Gargalovic PS, Lusis AJ, Binder BR, Bochkov VN (2008) ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response. Blood 112:330–339

    Article  PubMed  CAS  Google Scholar 

  22. Roybal CN, Yang S, Sun CW, Hurtado D, Vander Jagt DL, Townes TM, Abcouwer SF (2004) Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 279:14844–14852

    Article  PubMed  CAS  Google Scholar 

  23. Levy AP, Levy NS, Goldberg MA (1996) Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 271:2746–2753

    Article  PubMed  CAS  Google Scholar 

  24. Pages G, Berra E, Milanini J, Levy AP, Pouyssegur J (2000) Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. J biol chem 275:26484–26491

    Article  PubMed  CAS  Google Scholar 

  25. Liang SH, Zhang W, McGrath BC, Zhang P, Cavener DR (2006) PERK (eIF2alpha kinase) is required to activate the stress-activated MAPKs and induce the expression of immediate-early genes upon disruption of ER calcium homoeostasis. Biochem J 393:201–209

    Article  PubMed  CAS  Google Scholar 

  26. Yun H, Lee M, Kim SS, Ha J (2005) Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. J Biol Chem 280:9963–9972

    Article  PubMed  CAS  Google Scholar 

  27. Yen ML, Su JL, Chien CL, Tseng KW, Yang CY, Chen WF, Chang CC, Kuo ML (2005) Diosgenin induces hypoxia-inducible factor-1 activation and angiogenesis through estrogen receptor-related phosphatidylinositol 3-kinase/Akt and p38 mitogen-activated protein kinase pathways in osteoblasts. Mole Pharmacol 68:1061–1073

    Article  CAS  Google Scholar 

  28. Ozawa K, Tsukamoto Y, Hori O, Kitao Y, Yanagi H, Stern DM, Ogawa S (2001) Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. Cancer Res 61:4206–4213

    PubMed  CAS  Google Scholar 

  29. Kotch LE, Iyer NV, Laughner E, Semenza GL (1999) Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol 209:254–267

    Article  PubMed  CAS  Google Scholar 

  30. Peng J, Zhang L, Drysdale L, Fong GH (2000) The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proceedings of the national academy of sciences of the United States of America 97:8386–8391

    Article  PubMed  CAS  Google Scholar 

  31. Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977

    Article  PubMed  CAS  Google Scholar 

  32. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nature Rev Cancer 7:834–846

    Article  CAS  Google Scholar 

  33. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  PubMed  CAS  Google Scholar 

  34. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu J, Kaufman RJ, Chevet E, Bikfalvi A, Moenner M (2007) IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 67:6700–6707

    Article  PubMed  CAS  Google Scholar 

  35. Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, Shuman MA (2000) Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2:306–314

    Article  PubMed  CAS  Google Scholar 

  36. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer cell 15:220–231

    Article  PubMed  CAS  Google Scholar 

  37. Saidi A, Hagedorn M, Allain N, Verpelli C, Sala C, Bello L, Bikfalvi A, Javerzat S (2009) Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness. Int J Cancer. J Int Cancer 125:1054–1064

    Article  CAS  Google Scholar 

  38. Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, Le QT, Koong AC (2004) XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 64:5943–5947

    Article  PubMed  CAS  Google Scholar 

  39. Blais JD, Addison CL, Edge R, Falls T, Zhao H, Wary K, Koumenis C, Harding HP, Ron D, Holcik M, Bell JC,(2006) Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mole Cell Biol 26:9517–9532

    Article  CAS  Google Scholar 

  40. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  PubMed  CAS  Google Scholar 

  41. Marjon PL, Bobrovnikova-Marjon EV, Abcouwer SF (2004) Expression of the pro-angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 by human breast carcinomas is responsive to nutrient deprivation and endoplasmic reticulum stress. Mol Cancer 3:4

    Article  PubMed  Google Scholar 

  42. Mizukami Y, Kohgo Y, Chung DC (2007) Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin Cancer Res 13:5670–5674

    Article  PubMed  CAS  Google Scholar 

  43. Jiang HY, Wek SA, McGrath BC, Scheuner D, Kaufman RJ, Cavener DR, Wek RC (2003) Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol 23:5651–5663

    Article  PubMed  CAS  Google Scholar 

  44. Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161–10168

    Article  PubMed  CAS  Google Scholar 

  45. Hughes CS, Shen JW, Subjeck JR (1989) Resistance to etoposide induced by three glucose-regulated stresses in Chinese hamster ovary cells. Cancer Res 49:4452–4454

    PubMed  CAS  Google Scholar 

  46. Shen J, Hughes C, Chao C, Cai J, Bartels C, Gessner T, Subjeck J (1987) Coinduction of glucose-regulated proteins and doxorubicin resistance in Chinese hamster cells. Proc Natl Acad Sci U S A 84:3278–3282

    Article  PubMed  CAS  Google Scholar 

  47. Shen JW, Subjeck JR, Lock RB, Ross WE (1989) Depletion of topoisomerase II in isolated nuclei during a glucose-regulated stress response. Mol Cell Biol 9:3284–3291

    PubMed  CAS  Google Scholar 

  48. Lin ZP, Boller YC, Amer SM, Russell RL, Pacelli KA, Patierno SR, Kennedy KA (1998) Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance. Cancer Res 58:3059–3065

    PubMed  CAS  Google Scholar 

  49. Nitiss JL, Wang JC (1996) Mechanisms of cell killing by drugs that trap covalent complexes between DNA topoisomerases and DNA. Mol Pharmacol 50:1095–1102

    PubMed  CAS  Google Scholar 

  50. Yun J, Tomida A, Andoh T, Tsuruo T (2004) Interaction between glucose-regulated destruction domain of DNA topoisomerase IIalpha and MPN domain of Jab1/CSN5. J Biol Chem 279:31296–31303

    Article  PubMed  CAS  Google Scholar 

  51. Oono K, Yoneda T, Manabe T, Yamagishi S, Matsuda S, Hitomi J, Miyata S, Mizuno T, Imaizumi K, Katayama T, Tohyama M (2004) JAB1 participates in unfolded protein responses by association and dissociation with IRE1. Neurochem Int 45:765–772

    Article  PubMed  CAS  Google Scholar 

  52. Brewer JW, Diehl JA (2000) PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A 97:12625–12630

    Article  PubMed  CAS  Google Scholar 

  53. Hsu JL, Chiang PC, Guh JH (2009) Tunicamycin induces resistance to camptothecin and etoposide in human hepatocellular carcinoma cells: role of cell-cycle arrest and GRP78. Naunyn Schmiedebergs Arch Pharmacol 380:373–382

    Article  PubMed  CAS  Google Scholar 

  54. Reddy RK, Mao C, Baumeister P, Austin RC, Kaufman RJ, Lee AS (2003) 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 278:20915–20924

    Article  PubMed  CAS  Google Scholar 

  55. Ranganathan AC, Zhang L, Adam AP, Aguirre-Ghiso JA (2006) Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 66:1702–1711

    Article  PubMed  CAS  Google Scholar 

  56. Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yokota T, Goldsmith PC, Ellerby LM, Ellerby HM, Bredesen DE (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett 514:122–128

    Article  PubMed  CAS  Google Scholar 

  57. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332

    Article  PubMed  CAS  Google Scholar 

  58. Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111

    Article  PubMed  CAS  Google Scholar 

  59. Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H, Haga N (2003) Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci 94:15–21

    Article  PubMed  CAS  Google Scholar 

  60. Cascorbi I (2011) P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 201:261–283

    Article  PubMed  CAS  Google Scholar 

  61. Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville MP, Bours V (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22:90–97

    Article  PubMed  CAS  Google Scholar 

  62. Sukhai M, Piquette-Miller M (2000) Regulation of the multidrug resistance genes by stress signals. J Pharm Pharm Sci 3:268–280

    PubMed  CAS  Google Scholar 

  63. Nakanishi C, Toi M (2005) Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5:297–309

    Article  PubMed  CAS  Google Scholar 

  64. Kennedy BP, Soravia C, Moffat J, Xia L, Hiruki T, Collins S, Gallinger S, Bapat B (1998) Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal adenomas from familial adenomatous polyposis patients. Cancer Res 58:500–503

    PubMed  CAS  Google Scholar 

  65. Pearce HL, Safa AR, Bach NJ, Winter MA, Cirtain MC, Beck WT (1989) Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc Natl Acad Sci U S A 86:5128–5132

    Article  PubMed  CAS  Google Scholar 

  66. Pahl HL, Baeuerle PA (1995) A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B. EMBO J 14:2580–2588

    PubMed  CAS  Google Scholar 

  67. Boller YC, Brandes LM, Russell RL, Lin ZP, Patierno SR, Kennedy KA (2000) Prostaglandin A1 inhibits stress-induced NF-kappaB activation and reverses resistance to topoisomerase II inhibitors. Oncol Res 12:383–395

    PubMed  CAS  Google Scholar 

  68. Brandes LM, Lin ZP, Patierno SR, Kennedy KA (2001) Reversal of physiological stress-induced resistance to topoisomerase II inhibitors using an inducible phosphorylation site-deficient mutant of I kappa B alpha. Mol Pharmacol 60:559–567

    PubMed  CAS  Google Scholar 

  69. Ledoux S, Yang R, Friedlander G, Laouari D (2003) Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res 63:7284–7290

    PubMed  CAS  Google Scholar 

  70. Kraus M, Malenke E, Gogel J, Muller H, Ruckrich T, Overkleeft H, Ovaa H, Koscielniak E, Hartmann JT, Driessen C (2008) Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis. Mol Cancer Ther 7:1940–1948

    Article  PubMed  CAS  Google Scholar 

  71. Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS Jr, Weichold FF (2002) Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 99:3771–3779

    Article  PubMed  CAS  Google Scholar 

  72. Ikezoe T, Hisatake Y, Takeuchi T, Ohtsuki Y, Yang Y, Said JW, Taguchi H, Koeffler HP (2004) HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 64:7426–7431

    Article  PubMed  CAS  Google Scholar 

  73. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J (1999) HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 57:1147–1152

    Article  PubMed  CAS  Google Scholar 

  74. Gutmann H, Fricker G, Drewe J, Toeroek M, Miller DS (1999) Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol 56:383–389

    PubMed  CAS  Google Scholar 

  75. Rittmann-Grauer LS, Yong MA, Sanders V, Mackensen DG (1992) Reversal of Vinca alkaloid resistance by anti-P-glycoprotein monoclonal antibody HYB-241 in a human tumor xenograft. Cancer Res 52:1810–1816

    PubMed  CAS  Google Scholar 

  76. Martin C, Berridge G, Higgins CF, Callaghan R (1997) The multi-drug resistance reversal agent SR33557 and modulation of vinca alkaloid binding to P-glycoprotein by an allosteric interaction. Br J Pharmacol 122:765–771

    Article  PubMed  CAS  Google Scholar 

  77. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A 99:15387–15392

    Article  PubMed  CAS  Google Scholar 

  78. Jordan MA, Thrower D, Wilson L (1991) Mechanism of inhibition of cell proliferation by Vinca alkaloids. Cancer Res 51:2212–2222

    PubMed  CAS  Google Scholar 

  79. Jiang CC, Yang F, Thorne RF, Zhu BK, Hersey P, Zhang XD (2009) Human melanoma cells under endoplasmic reticulum stress acquire resistance to microtubule-targeting drugs through XBP-1-mediated activation of Akt. Neoplasia 11:436–447

    PubMed  CAS  Google Scholar 

  80. Yamada M, Tomida A, Yun J, Cai B, Yoshikawa H, Taketani Y, Tsuruo T (1999) Cellular sensitization to cisplatin and carboplatin with decreased removal of platinum-DNA adduct by glucose-regulated stress. Cancer Chemother Pharmacol 44:59–64

    Article  PubMed  CAS  Google Scholar 

  81. Gaddameedhi S, Chatterjee S (2009) Association between the unfolded protein response, induced by 2-deoxyglucose, and hypersensitivity to cisplatin: a mechanistic study employing molecular genomics. J Cancer Res Ther 5(Suppl 1):S61–66

    PubMed  CAS  Google Scholar 

  82. Fribley AM, Evenchik B, Zeng Q, Park BK, Guan JY, Zhang H, Hale TJ, Soengas MS, Kaufman RJ, Wang CY (2006) Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem 281:31440–31447

    Article  PubMed  CAS  Google Scholar 

  83. Mandic A, Hansson J, Linder S, Shoshan MC (2003) Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem 278:9100–9106

    Article  PubMed  CAS  Google Scholar 

  84. Belfi CA, Chatterjee S, Gosky DM, Berger SJ, Berger NA (1999) Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation. Biochem Biophys Res Commun 257:361–368

    Article  PubMed  CAS  Google Scholar 

  85. Lust S, Vanhoecke B, Van Gele M, Philippe J, Bracke M, Offner F (2010) The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562. Mol Nutr Food Res 54:823–832

    Article  PubMed  CAS  Google Scholar 

  86. Jackson RJ, Hellen CU, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11:113–127

    Article  PubMed  CAS  Google Scholar 

  87. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745

    Article  PubMed  CAS  Google Scholar 

  88. Dever TE (2002) Gene-specific regulation by general translation factors. Cell 108:545–556

    Google Scholar 

  89. Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  PubMed  CAS  Google Scholar 

  90. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108

    Article  PubMed  CAS  Google Scholar 

  91. Ma Y, Hendershot LM (2003) Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem 278:34864–34873

    Article  PubMed  CAS  Google Scholar 

  92. Novoa I, Zeng H, Harding HP, Ron D (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 153:1011–1022

    Article  PubMed  CAS  Google Scholar 

  93. Brewer JW, Hendershot LM, Sherr CJ, Diehl JA (1999) Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression. Proc Natl Acad Sci U S A 96:8505–8510

    Article  PubMed  CAS  Google Scholar 

  94. Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, Kasuga M, Nishimoto I, Avruch J (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272:26457–26463

    Article  PubMed  CAS  Google Scholar 

  95. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318

    Article  PubMed  CAS  Google Scholar 

  96. Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3 K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328

    Article  PubMed  CAS  Google Scholar 

  97. Robert F, Pelletier J (2009) Translation initiation: a critical signalling node in cancer. Expert Opin Ther Targets 13:1279–1293

    Article  PubMed  CAS  Google Scholar 

  98. Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40:310–322

    Article  PubMed  CAS  Google Scholar 

  99. Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10:2305–2316

    Article  PubMed  CAS  Google Scholar 

  100. Dowling RJ, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E, Wang X, Larsson O, Selvaraj A, Liu Y, Kozma SC, Thomas G, Sonenberg N (2010) mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328:1172–1176

    Article  PubMed  CAS  Google Scholar 

  101. Reiling JH, Sabatini DM (2006) Stress and mTORture signaling. Oncogene 25:6373–6383

    Article  PubMed  CAS  Google Scholar 

  102. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35

    Article  PubMed  CAS  Google Scholar 

  103. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189

    Article  PubMed  CAS  Google Scholar 

  104. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25:903–915

    Article  PubMed  CAS  Google Scholar 

  105. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–886

    Article  PubMed  CAS  Google Scholar 

  106. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302

    Article  PubMed  CAS  Google Scholar 

  107. Yang Q, Inoki K, Ikenoue T, Guan KL (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20:2820–2832

    Article  PubMed  CAS  Google Scholar 

  108. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405:513–522

    Article  PubMed  CAS  Google Scholar 

  109. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  110. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168

    Article  PubMed  CAS  Google Scholar 

  111. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032

    Article  PubMed  CAS  Google Scholar 

  112. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38

    Article  PubMed  CAS  Google Scholar 

  113. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  PubMed  CAS  Google Scholar 

  114. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657

    Article  PubMed  CAS  Google Scholar 

  115. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162

    Article  PubMed  CAS  Google Scholar 

  116. Chalhoub N, Baker SJ (2009) PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4:127–150

    Article  PubMed  CAS  Google Scholar 

  117. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  PubMed  CAS  Google Scholar 

  118. Gebauer F, Hentze MW (2004) Molecular mechanisms of translational control. Nat Rev Mol Cell Biol 5:827–835

    Article  PubMed  CAS  Google Scholar 

  119. Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N (1994) Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5’-cap function. Nature 371:762–767

    Article  PubMed  CAS  Google Scholar 

  120. Marcotrigiano J, Gingras AC, Sonenberg N, Burley SK (1999) Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 3:707–716

    Article  PubMed  CAS  Google Scholar 

  121. Haghighat A, Mader S, Pause A, Sonenberg N (1995) Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J 14:5701–5709

    PubMed  CAS  Google Scholar 

  122. Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68:631–634

    Article  PubMed  CAS  Google Scholar 

  123. Parsyan A, Svitkin Y, Shahbazian D, Gkogkas C, Lasko P, Merrick WC, Sonenberg N (2011) mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol 12:235–245

    Article  PubMed  CAS  Google Scholar 

  124. Graff JR, Zimmer SG (2003) Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin Exp Metastasis 20:265–273

    Article  PubMed  CAS  Google Scholar 

  125. Fischer PM (2009) Cap in hand: targeting eIF4E. Cell Cycle 8:2535–2541

    Article  PubMed  CAS  Google Scholar 

  126. Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U (2010) The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med 16:429–437

    Article  PubMed  CAS  Google Scholar 

  127. Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR (2010) A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat Med 16:438–445

    Article  PubMed  CAS  Google Scholar 

  128. Kang YJ, Lu MK, Guan KL (2011) The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis. Cell Death Differ 18:133–144

    Article  PubMed  CAS  Google Scholar 

  129. Qin L, Wang Z, Tao L, Wang Y (2010) ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6:239–247

    Article  PubMed  CAS  Google Scholar 

  130. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461

    Article  PubMed  CAS  Google Scholar 

  131. Whitney ML, Jefferson LS, Kimball SR (2009) ATF4 is necessary and sufficient for ER stress-induced upregulation of REDD1 expression. Biochem Biophys Res Commun 379:451–455

    Article  PubMed  CAS  Google Scholar 

  132. Jin HO, Seo SK, Woo SH, Kim ES, Lee HC, Yoo DH, An S, Choe TB, Lee SJ, Hong SI, Rhee CH, Kim JI, Park IC (2009) Activating transcription factor 4 and CCAAT/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress. Free Radic Biol Med 46:1158–1167

    Article  PubMed  CAS  Google Scholar 

  133. Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tashiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J, Sonenberg N, Oka Y (2008) ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Cell Metab 7:269–276

    Article  PubMed  CAS  Google Scholar 

  134. Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ (2000) Molecular genetic advances in tuberous sclerosis. Hum Genet 107:97–114

    Article  PubMed  CAS  Google Scholar 

  135. Lazaris-Karatzas A, Montine KS, Sonenberg N (1990) Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5’ cap. Nature 345:544–547

    Article  PubMed  CAS  Google Scholar 

  136. Zimmer SG, DeBenedetti A, Graff JR (2000) Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res 20:1343–1351

    PubMed  CAS  Google Scholar 

  137. Koromilas AE, Lazaris-Karatzas A, Sonenberg N (1992) mRNAs containing extensive secondary structure in their 5’ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J 11:4153–4158

    PubMed  CAS  Google Scholar 

  138. Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C, Pandolfi PP (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10:484–486

    Article  PubMed  CAS  Google Scholar 

  139. Coleman LJ, Peter MB, Teall TJ, Brannan RA, Hanby AM, Honarpisheh H, Shaaban AM, Smith L, Speirs V, Verghese ET, McElwaine JN, Hughes TA (2009) Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity. Br J Cancer 100:1393–1399

    Article  PubMed  CAS  Google Scholar 

  140. De Benedetti A, Graff JR (2004) eIF-4E expression and its role in malignancies and metastases. Oncogene 23:3189–3199

    Article  PubMed  CAS  Google Scholar 

  141. Silvera D, Formenti SC, Schneider RJ (2010) Translational control in cancer. Nat Rev Cancer 10:254–266

    Article  PubMed  CAS  Google Scholar 

  142. O’Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H, Polsky D, Pavlick AC, Rosen N, Bhardwaj N, Mills G, Osman I (2009) Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res 15:2872–2878

    Article  PubMed  Google Scholar 

  143. Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, Yang W, Smith TL, Shi D, Yu D (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10:6779–6788

    Article  PubMed  CAS  Google Scholar 

  144. Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, Vanpatten K, Highstrom L, Pestano GA, Nagle RB (2006) Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 66:1203–1212

    Article  PubMed  CAS  Google Scholar 

  145. Castellvi J, Garcia A, Ruiz-Marcellan C, Hernandez-Losa J, Peg V, Salcedo M, Gil-Moreno A, Ramon y Cajal S (2009) Cell signaling in endometrial carcinoma: phosphorylated 4E-binding protein-1 expression in endometrial cancer correlates with aggressive tumors and prognosis. Hum Pathol 40:1418–1426

    Article  PubMed  CAS  Google Scholar 

  146. Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J, Ramon y Cajal S (2006) Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107:1801–1811

    Article  PubMed  CAS  Google Scholar 

  147. Shuda M, Kwun HJ, Feng H, Chang Y, Moore PS (2011) Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. J Clin Investig 121:3623–3634

    Article  PubMed  CAS  Google Scholar 

  148. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

    Article  PubMed  CAS  Google Scholar 

  149. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  150. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Sci Signal 2:pe24

    Article  PubMed  Google Scholar 

  151. Brachmann S, Fritsch C, Maira SM, Garcia-Echeverria C (2009) PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr Opin Cell Biol 21:194–198

    Article  PubMed  CAS  Google Scholar 

  152. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32–50

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Sonia Pereira for her successful efforts in bringing our ideas to life in the figures, Ms. Melissa Mann for scientific input, and Dr. Joel Otero for technical assistance. This work was supported by NIH Grant P01CA023099 (LMH), the Hal and Alma Reagan Fellowship (ERP), the Cancer Center CORE Grant CA21765, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital.

Author information

Authors and Affiliations

  1. Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, 38105, Memphis, TN, USA

    Ethel R. Pereira, Amanda M. Preston & Linda M. Hendershot

  2. Department of Biological Sciences, University of Tennessee Health Sciences Center, Memphis, TN, USA

    Ethel R. Pereira & Linda M. Hendershot

Authors
  1. Ethel R. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda M. Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda M. Hendershot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda M. Hendershot .

Editor information

Editors and Affiliations

  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

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Pereira, E., Preston, A., Hendershot, L. (2012). UPR Activation in Cancer Cells: A Double-Edged Sword. 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_17

Download citation

Publish with us

Policies and ethics

Search

Navigation