DISCOVERIES (ISSN 2359-7232), 2014, January-March

CITATION:

Wu L, Chou M, Zhu S. Unfolded Protein Response and Cancer. Discoveries 2014, Jan-Mar; 2(1): e10. DOI: 10.15190/d.2014.2;

Submitted: February 26, 2014; Published after revision:March 14, 2014

GO BACK to 2014, January-March issue
GO BACK to DISCOVERIES

Unfolded Protein Response and Cancer

Lihua Wu (1), Mary Chou (2), Shudong Zhu (1,*)

Affiliation:
(1) School of Life Sciences, State Key Laboratory of Medical Genetics, Central South University, Changsha, China, (2) Advanced Orthomolecular Research Inc., Calgary, Canada

*Correspondence should be addressed to: Shudong Zhu, PhD, School of Life Sciences, Central South University, 172, TongZiPo Rd., Changsha, China; Phone: 731-8265-0460; Email: shudongzhu@csu.edu.cn

Abstract

Physiological stresses, such as hypoxia and oxidative stress, induce protein misfolding in the endoplasmic reticulum (ER). If proteasome degradation fails to remove the misfolded proteins, these proteins accumulate in the ER, triggering the unfolded protein response (UPR). UPR involves a series of responses, such as the suppression of global protein synthesis and the select expression of a set of proteins to reduce ER stress and restore the homeostasis of ER.  

In different stages of tumor development, hypoxia occurs and UPR is initiated. The roles of UPR in cancer development are complex, involving angiogenesis, cell survival and proliferation. The current knowledge of the molecular mechanisms involved in UPR, particularly its role in the development of cancer, is discussed

Access full text of the manuscript here: See full text (pdf)

References

1. Tagliavacca L, Caretti A, Bianciardi P and Samaja M. In vivo up-regulation of the unfolded protein response after hypoxia. Biochim Biophys Acta 2012; 1820: 900-906. PMID: 22450154
2. Bertolotti A, Zhang Y, Hendershot LM, Harding HP and Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2: 326–332. PMID: 10854322
3. Yoshida H, Matsui T, Yamamoto A, Okada T and Mori K XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107: 881–891. PMID: 11779464
4. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y and Dynlacht BD. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 2007; 27, 53–66. PMID: 17612490
5. Hetz C and Glimcher LH. Fine-tuning of the unfolded protein response: assembling the IRE1a interactome. Mol Cell 2009; 35, 551–561. PMID: 19748352
6. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, LaVail MM and Walter P. IRE1 signaling affects cell fate during the unfolded protein response. Science 2007; 318: 944–949. PMID: 17991856
7. Kurata M, Yamazaki Y, Kanno Y, Ishibashi S, Takahara T, Kitagawa M and Nakamura T. Anti-apoptotic function of Xbp1 as an IL-3 signaling molecule in hematopoietic cells. Cell Death Dis 2011; 10: e118. PMID: 21368889
8. Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M and Ron D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 1998; 17: 5708–5717. PMID: 9755171
9. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP and Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287: 664–666. PMID: 10650002
10. Chen F. JNK-induced apoptosis, compensatory growth, and cancer stem cells. Cancer Res 2012; 72: 379-86. PMID: 22253282
11. Dumitrascu GR and Bucur O. Critical physiological and pathological functions of Forkhead Box O tumor suppressors. Discoveries 2013; 1: e5. DOI: 10.15190/d.2013.5
12. Calautti E. Akt modes of stem cell regulation: more than meets the eye? Discoveries 2013; 1: e8. DOI: 10.15190/d.2013.8
13. Hu P, Han Z, Couvillon AD, Kaufman RJ and Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1a-mediated NF-jB activation and down-regulation of TRAF2 expression. Mol Cell Biol 2006; 26: 3071–3084. PMID: 16581782
14. Hollien J, Lin JH, Li H, Stevens N, Walter P and Weissman JS. Regulated Ire1 dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009; 186, 323–331. PMID: 19651891
15. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, et al. IRE1a cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase 2. Science 2012; 338, 818–822. PMID: 23042294
16. Han D, Lerner AG, Walle LV, Upton JP, Xu W, Hagen A, et al. IRE1a kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 2009; 138: 562–575. PMID: 19665977
17. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1a. Science 2006; 312: 572–576. PMID: 16645094
18. Rodriguez DA, Zamorano S, Lisbona F, Rojas-Rivera D, Urra H, Cubillos-Ruiz JR, et al. BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1[alpha]. EMBO J 2012; 31: 2322–2335. PMID: 22510886
19. Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C and Samali A. HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1a-XBP1 signaling through a physical interaction. PLoS Biol 2010; 8: e1000410. PMID: 20625543
20. Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007; 11: 349-360. PMID: 17418411
21. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, et al. Identification of an IRE1a endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011; 117: 1311-1314. PMID: 21081713
22. Auf G, Jabouille A, Guerit S, Pineau R, Delugin M, Bouchecareilh M, et al. Inositol-requiring enzyme 1a is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci USA 2010; 107: 15553-15558. PMID: 20702765
23. Romero-Ramirez L, Cao H, Regalado MP, Kambham N, Siemann D, Kim JJ, Le QT and Koong AC. X-Box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Transl Oncol 2009; 2: 31-38. PMID: 19252749
24. Harding HP, Zhang Y and Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999; 397: 271–274. PMID: 9930704
25. Diehl JA, Fuchs SY and Koumenis C. The cell biology of the unfolded protein response. Gastroenterology 2011; 141: 38–41. 41 e31–32. PMID: 21620842
26. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP and Ron D. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 2004; 18: 3066-3077. PMID: 15601821
27. Novoa,I, Zeng H, Harding HP and Ron D. Feedback inhibition of the unfolded protein response by GADD34 mediated dephosphorylation of eIF2a. J Cell Biol 2001; 153: 1011–1022. PMID: 11381086
28. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, et al.. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 2010; 120: 127–141. PMID: 20038797
29. Hoyer-Hansen M and Jaattela M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 2007; 14: 1576–1582. PMID: 17612585
30. Chakrabarti A, Chen AW and Varner JC. A review of the mammalian unfolded protein response. Biotechnol Bioeng 2011; 108: 2777-2793. PMID: 21809331
31. Teske BF, Wek SA, Bunpo P, Cundiff JK, McClintick JN, Anthony TG and Wek RC. The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Mol Biol Cell 2011; 22: 4390–4405. PMID: 21917591
32. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG and Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 2005; 24: 3470-3481. PMID: 16148948
33. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, Cavener D and Diehl JA. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 2010; 29: 3881-3895. PMID: 20453876
34. Ranganathan AC, Ojha S, Kourtidis A, Conklin DS and Aguirre Ghiso JA. Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Res 2008; 68: 3260-3268. PMID: 18451152
35. Michalak M, Groenendyk J, Szabo E, Gold LI and Opas M. Calreticulin, a multi-process calciumbuffering chaperone of the endoplasmic reticulum. Biochem J 2009; 417: 651–666. PMID: 19133842
36. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 2009; 28: 578–590. PMID: 19165151
37. Ye J, Rawson RB, Komuro R, Chen X, Dave´ UP, Prywes R, Brown MS and Goldstein JL. ER stress induces cleavage of membranebound ATF6 by the same proteases that process SREBPs. Mol Cell 2000; 6: 1355–1364. PMID: 11163209
38. Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, Yates JR, Su AI, Kelly JW and Wiseman RL. Stressindependent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013; 3: 1279-1292. PMID: 23583182
39. Schewe DM and Aguirre-Ghiso JA. ATF6a-RHEB-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci USA 2008; 105: 10519-10524. PMID: 18650380
40. Papa L and Germain D. SirT3 regulates the mitochondrial unfolded protein response. Mol Cell Biol 2014; 34: 699-710. PMID: 24324009
41. Bartoszewska S, Kochan K, Madanecki P, Piotrowski A, Ochocka R, Collawn JF and Bartoszewski R. Regulation of the unfolded protein response by microRNAs. Cell Mol Biol Lett 2013; 18:555-578. PMID: 24092331
42. Nana-Sinkam SP and Choi AM. Epigenetics and the unfolded protein response in the lung: emerging role for microRNAs. Am J Respir Crit Care Med 2014; 189: 239-240. PMID: 24484325
43. Cattaneo M, Baronchelli S, Schiffer D, Mellai M, Caldera V, Saccani GJ, Dalpra L, Daga A, Orlandi R, DeBlasio P and Biunno I. Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid. J Biol Chem 2014; 289: 2826-38. PMID: 24311781
44. Brem GJ, Mylonas I and Brüning A. Eeyarestatin causes cervical cancer cell sensitization to bortezomib treatment by augmenting ER stress and CHOP expression. Gynecol Oncol 2013; 128: 383-390. PMID: 23107612

GO BACK to 2014, January-March issue
GO BACK to DISCOVERIES
MEET OUR EDITORIAL BOARD
SUBMIT A MANUSCRIPT

Email us at info@discoveriesjournals.org if you have any questions.