Glucose-regulated proteins in cancer: Molecular mechanisms and therapeutic potential

Nature Reviews Cancer

Volumn 14, Issue 4, 2014, Pages 263-276

  Lee, Amy S ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CALCIUM ION; CASPASE 7; CHAPERONE; CYTOTOXIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR 2; GLUCOSE REGULATED PROTEIN; GLUCOSE REGULATED PROTEIN 78; GLUCOSE REGULATED PROTEIN 94; GLYCOSYLPHOSPHATIDYLINOSITOL; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN BAX; PROTEIN BCL 2; PROTEIN KINASE B; SOMATOMEDIN C RECEPTOR;

ALTERNATIVE RNA SPLICING; ANCHORAGE INDEPENDENT GROWTH; ANGIOGENESIS; APOPTOSIS; BINDING AFFINITY; CALCIUM HOMEOSTASIS; CELL PROLIFERATION; ENDOPLASMIC RETICULUM STRESS; ENZYME REGULATION; FIBROBLAST; GENE OVEREXPRESSION; HEMATOPOIETIC STEM CELL; IMMUNE EVASION; INFLAMMATION; INTRACELLULAR SIGNALING; METASTASIS; MITOCHONDRION; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INDUCTION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; TUMOR INVASION; TUMOR VASCULARIZATION; UNFOLDED PROTEIN RESPONSE; UPREGULATION; VACCINATION;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL PROLIFERATION; DRUG RESISTANCE, NEOPLASM; ENDOPLASMIC RETICULUM; GENE EXPRESSION REGULATION, NEOPLASTIC; HSP70 HEAT-SHOCK PROTEINS; HUMANS; MEMBRANE PROTEINS; MITOCHONDRIA; NEOPLASMS; NEOPLASTIC STEM CELLS; STRESS, PHYSIOLOGICAL;

EID: 84897036337     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3701     Document Type: Review

References (199)

1. Ni, M. & Lee, A. S. ER chaperones in mammalian development and human diseases. FEBS Lett. 581, 3641-3651 (2007).
2. Wang, X. Y. & Subjeck, J. R. High molecular weight stress proteins: Identification, cloning and utilisation in cancer immunotherapy. Int. J. Hyperthermia 29, 364-375 (2013).
3. Wadhwa, R., Taira, K. & Kaul, S. C. An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where? Cell Stress Chaperones 7, 309-316 (2002).
4. Marzec, M., Eletto, D. & Argon, Y. GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim. Biophys. Acta 1823, 774-787 (2012).
5. Lee, A. S. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 67, 3496-3499 (2007).
6. Miao, Y. R. et al. Inhibition of established micrometastases by targeted drug delivery via cell surface-Associated GRP78. Clin. Cancer Res. 19, 2107-2116 (2013).
7. Wang, M., Wey, S., Zhang, Y., Ye, R. & Lee, A. S. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid. Redox Signal. 11, 2307-2316 (2009).
8. Kusaczuk, M. & Cechowska-Pasko, M. Molecular chaperone ORP150 in ER stress-related diseases. Curr. Pharm. Des. 19, 2807-2818 (2013).
9. Behnke, J. & Hendershot, L. M. The large Hsp70 Grp170 binds to unfolded protein substrates in vivo with a regulation distinct from conventional Hsp70s. J. Biol. Chem. 289, 2899-2907 (2013).
10. Wadhwa, R. et al. Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Exp. Cell Res. 274, 246-253 (2002).
11. Ni, M., Zhang, Y. & Lee, A. S. Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem. J. 434, 181-188 (2011).
12. Gonzalez-Gronow, M., Selim, M. A., Papalas, J. & Pizzo, S. V. GRP78: a multifunctional receptor on the cell surface. Antioxid. Redox Signal. 11, 2299-2306 (2009).
13. Sato, M., Yao, V. J., Arap, W. & Pasqualini, R. GRP78 signaling hub a receptor for targeted tumor therapy. Adv. Genet. 69, 97-114 (2010).
14. Gray, P. C. & Vale, W. Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis. FEBS Lett. 586, 1836-1845 (2012).
15. Zhang, Y., Liu, R., Ni, M., Gill, P. & Lee, A. S. Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP. J. Biol. Chem. 285, 15065-15075 (2010).
16. Zhang, Y. et al. Cancer cells resistant to therapy promote cell surface relocalization of GRP78 which complexes with PI3K and enhances PI(3, 4, 5)P3 production. PLoS ONE 8, e80071 (2013).
17. Liu, R. et al. Monoclonal antibody against cell surface GRP78 as a novel agent in suppressing PI3K/AKT signaling, tumor growth and metastasis. Clin. Cancer Res. 19, 6802-6811 (2013).
18. Pfaffenbach, K. T. et al. GRP78/BiP is a novel downstream target of IGF-1 receptor mediated signaling. J. Cell. Physiol. 227, 3803-3811 (2012).
19. Gray, M. J. et al. AKT inhibition mitigates GRP78 (glucose-regulated protein) expression and contribution to chemoresistance in endometrial cancers. Int. J. Cancer 133, 21-30 (2013).
20. Luo, B. & Lee, A. S. The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene 32, 805-818 (2013).
21. Li, J. & Lee, A. S. Stress induction of GRP78/BiP and its role in cancer. Curr. Mol. Med. 6, 45-54 (2006).
22. Yun, C. O. & Wadhwa, R. in Mortalin Biology: Life, Stress and Death: Life, Stress and Death. Ch.18 (eds Kaul, S. C. & Wadhwa, R.) (Springer, 2012).
23. Srivastava, P. K. Identification of chaperones as essential components of the tumor rejection moieties of cancers. Cancer Immun. 12, 5 (2012).
24. Mori, K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451-454 (2000).
25. Chang, S. C., Erwin, A. E. & Lee, A. S. Glucose-regulated protein (GRP94 and GRP78) genes share common regulatory domains and are coordinately regulated by common trans-Acting factors. Mol. Cell. Biol. 9, 2153-2162 (1989).
26. Ma, Y. & Hendershot, L. M. The role of the unfolded protein response in tumour development: friend or foe? Nature Rev. Cancer 4, 966-977 (2004).
27. Wu, J. & Kaufman, R. J. From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. 13, 374-384 (2006).
28. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell. Biol. 8, 519-529 (2007).
29. Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature Rev. Mol. Cell. Biol. 13, 89-102 (2012).
30. Luo, S., Baumeister, P., Yang, S., Abcouwer, S. F. & Lee, A. S. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through an upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J. Biol. Chem. 278, 37375-37385 (2003).
31. Lee, K. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 16, 452-466 (2002).
32. Li, J. et al. The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells. Cell Death Differ. 15, 1460-1471 (2008).
33. Wang, M. et al. Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis. Cell Death Differ. 17, 488-498 (2010).
34. Wey, S., Luo, B. & Lee, A. S. Acute inducible ablation of GRP78 reveals its role in hematopoietic stem cell survival, lymphogenesis and regulation of stress signaling. PLoS ONE 7, e39047 (2012).
35. Heijmans, J. et al. ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response. Cell. Rep. 3, 1128-1139 (2013).
36. Mathew, R. et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062-1075 (2009).
37. Baumeister, P., Dong, D., Fu, Y. & Lee, A. S. Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. Mol. Cancer Ther. 8, 1086-1094 (2009).
38. Pyrko, P., Schonthal, A. H., Hofman, F. M., Chen, T. C. & Lee, A. S. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res. 67, 9809-9816 (2007).
39. Dong, D. 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. 68, 498-505 (2008).
40. Verras, M., Papandreou, I., Lim, A. L. & Denko, N. C. Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol. Cell. Biol. 28, 7212-7224 (2008).
41. Misra, U. K., Gonzalez-Gronow, M., Gawdi, G. & Pizzo, S. V. The role of MTJ-1 in cell surface translocation of GRP78, a receptor for a 2-macroglobulin-dependent signaling. J. Immunol. 174, 2092-2097 (2005).
42. Burikhanov, R. et al. The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138, 377-388 (2009).
43. Misra, U. K. et al. The role of Grp 78 in cc 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction. J. Biol. Chem. 277, 42082-42087 (2002).
44. Misra, U. K. & Pizzo, S. V. Receptor-recognized a(2)-macroglobulin binds to cell surface-Associated GRP78 and activates mTORC1 and mTORC2 signaling in prostate cancer cells. PLoS ONE 7, e51735 (2012).
45. de Ridder, G. G., Gonzalez-Gronow, M., Ray, R. & Pizzo, S. V. Autoantibodies against cell surface GRP78 promote tumor growth in a murine model of melanoma. Melanoma Res. 21, 35-43 (2011).
46. Salmena, L, Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403-414 (2008).
47. Fu, Y. et al. Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc. Natl Acad. Sci. USA 105, 19444-19449 (2008).
48. Wey, S. et al. Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood 119, 817-825 (2012)
49. Shani, G. et al. GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor p signaling and enhance cell growth. Mol. Cell. Biol. 28, 666-677 (2008).
50. Kelber, J. A. et al. Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene 28, 2324-2336 (2009)
51. Wanderling, S. et al. GRP94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion. Mol. Biol. Cell 18, 3764-3775 (2007).
52. Liu, B. et al. Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway. Proc. Natl. Acad. Sci. USA 110, 6877-6882 (2013).
53. Hua, Y. et al. Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma. Clin. Cancer Res. 19, 6242-6251 (2013).
54. Morales, C. et al. Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res. 74, 446-459 (2014).
55. Dejeans, N. et al. Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence. Free Radic. Biol. Med. 52, 993-1002 (2012).
56. Kaul, S. C. et al. Malignant transformation of NIH3T3 cells by overexpression of mot-2 protein. Oncogene 17, 907-911 (1998).
57. Wadhwa, R. et al. Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J. Biol. Chem. 273, 29586-29591 (1998).
58. Mizukoshi, E. et al. Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin. Biochem. J. 343 461-466 (1999).
59. Rao, R. V. et al. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. 514, 122-128 (2002).
60. Reddy, R. K. 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. 278, 20915-20924 (2003).
61. Fu, Y., Li, J. & Lee, A. S. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen-starvation induced apoptosis. Cancer Res. 67, 3734-3740 (2007).
62. Zhou, H., Zhang, Y., Fu, Y., Chan, L. & Lee, A. S. Novel mechanism of anti-Apoptotic function of 78-kDa glucose-regulated protein (GRP78): endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J. Biol. Chem. 286, 25687-25696 (2011).
63. Ni, M., Zhou, H., Wey, S., Baumeister, P. & Lee, A. S. Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PLoS ONE 4, e6868 (2009).
64. Shu, C. W. et al. GRP78 and Raf-1 cooperatively confer resistance to endoplasmic reticulum stress-induced apoptosis. J. Cell. Physiol. 215, 627-635 (2008).
65. Luo, S., Mao, C., Lee, B. & Lee, A. S. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol. Cell. Biol. 26, 5688-5697 (2006).
66. Zhu, G. et al. GRP78 plays an essential role in adipogenesis and postnatal growth in mice. FASEB J. 27, 955-964 (2013).
67. Misra, U. K., Deedwania, R. & Pizzo, S. V. Activation and cross-talk between Akt, NF-κB, and unfolded protein response signaling in 1-LN prostate cancer cells consequent to ligation of cell surface-Associated GRP78. J. Biol. Chem. 281, 13694-13707 (2006).
68. Davidson, D. J. et al. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. Cancer Res. 65, 4663-4672 (2005).
69. Martin-Perez, R., Niwa, M. & Lopez-Rivas, A. ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2. Apoptosis 17, 349-363 (2012).
70. Cook, K. L. et al. Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res. 72, 3337-3349 (2012).
71. 2+-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. J. Biol. Chem. 274, 28476-28483 (1999).
72. Patel, P. D. et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nature Chem. Biol. 9, 677-684 (2013).
73. Namba, T. et al. Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells. Mol. Pharmacol. 71, 860-870 (2007).
74. Gao, Y. Y. et al. Implication of oxygen-regulated protein 150 (ORP150) in apoptosis induced by proteasome inhibitors in human thyroid cancer cells. J. Clin. Endocrinol. Metab. 95, E319-E326 (2010).
75. Sanson, M. et al. Oxidized low-density lipoproteins trigger endoplasmic reticulum stress in vascular cells: prevention by oxygen-regulated protein 150 expression. Circ. Res. 104, 328-336 (2009).
76. Sanson, M. et al. Oxygen-regulated protein-150 prevents calcium homeostasis deregulation and apoptosis induced by oxidized LDL in vascular cells. Cell Death Differ. 15, 1255-1265 (2008).
77. Virrey, J. J. et al. Stress chaperone GRP78/BiP confers chemoresistance to tumor-Associated endothelial cells. Mol. Cancer Res. 6, 1268-1275 (2008).
78. McFarland, B. C. et al. Plasminogen Kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1. Cancer Res. 69, 5537-5545 (2009).
79. Bhattacharjee, G. et al. Regulation of tissue factor-mediated initiation of the coagulation cascade by cell surface grp78. Arterioscler. Thromb. Vasc. Biol. 25, 1737-1743 (2005).
80. Philippova, M. et al. Identification of proteins associating with glycosylphosphatidylinositol-Anchored T-cadherin on the surface of vascular endothelial cells: role for Grp78/BiP in T-cadherin-dependent cell survival. Mol. Cell. Biol. 28, 4004-4017 (2008).
81. Gonzalez-Gronow, M. et al. Plasminogen structural domains exhibit different functions when associated with cell surface GRP78 or the voltage-dependent anion channel. J. Biol. Chem. 282, 32811-32820 (2007).
82. Katanasaka, Y. et al. Cancer antineovascular therapy with liposome drug delivery systems targeted to BiP/GRP78. Int. J. Cancer 127, 2685-2698 (2010).
83. Ozawa, K. et al. Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone. Cancer Res. 61, 4206-4213 (2001).
84. Fu, Y. & Lee, A. S. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol. Ther. 5, 741-744 (2006).
85. Sun, Q. et al. Expressions of GRP78 and Bax associate with differentiation, metastasis, and apoptosis in non-small cell lung cancer. Mol. Biol. Rep. 39, 6753-6761 (2012).
86. Daneshmand, S. et al. Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum. Pathol. 38, 1547-1552 (2007).
87. Zhang, J. et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin. Exp. Metastasis 23, 401-410 (2006).
88. Li, Z. et al. Cell-surface GRP78 facilitates colorectal cancer cell migration and invasion. Int. J. Biochem. Cell. Biol. 45, 987-994 (2013).
89. Dong, D. et al. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res. 71, 2848-2857 (2011).
90. Misra, U. K., Deedwania, R. & Pizzo, S. V. Binding of activated α2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J. Biol. Chem. 280, 26278-26286 (2005).
91. Zheng, H. C. et al. Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum. Pathol. 39, 1042-1049 (2008).
92. Hong, F., Liu, B., Chiosis, G., Gewirth, D. T. & Li, Z. α7 helix region of αI domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. J. Biol. Chem. 288, 18243-18248 (2013).
93. Yi, X. et al. Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol. Cell. Proteomics 7, 315-325 (2008).
94. Stojadinovic, A. et al. HYOU1/Orp150 expression in breast cancer. Med. Sci. Monit. 13, BR231-239 (2007).
95. Mahadevan, N. R. et al. Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc. Natl Acad. Sci. USA 108, 6561-6566 (2011).
96. Li, Z. & Li, Z. Glucose regulated protein 78: A critical link between tumor microenvironment and cancer hallmarks. Biochim. Biophys. Acta 1826, 13-22 (2012).
97. Hori, O. et al. Exposure of astrocytes to hypoxia/reoxygenation enhances expression of glucose-regulated protein 78 facilitating astrocyte release of the neuroprotective cytokine interleukin 6. J. Neurochem. 66, 973-979 (1996).
98. Jamora, C., Dennert, G. & Lee, A. S. Inhibition of tumor progression by suppression of stress protein GRP78/BiP induction in fibrosarcoma B/C10ME. Proc. Natl Acad. Sci. USA 93, 7690-7694 (1996).
99. Triantafilou, M., Fradelizi, D. & Triantafilou, K. Major histocompatibility class one molecule associates with glucose regulated protein (GRP) 78 on the cell surface. Hum. Immunol. 62, 764-770 (2001).
100. Misra, U. K., Chu, C. T., Rubenstein, D. S., Gawdi, G. & Pizzo, S. V. Receptor-recognized α 2-macroglobulin-methylamine elevates intracellular calcium, inositol phosphates and cyclic AMP in murine peritoneal macrophages. Biochem. J. 290, 885-891 (1993).
101. Misra, U. K. & Pizzo, S. V. Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways. PLoS ONE 8, e63150 (2013).
102. Oida, T. & Weiner, H. L. TGF-β induces surface LAP expression on murine CD4 T cells independent of Foxp3 induction. PLoS ONE 5, e15523 (2010)
103. Corrigall, V. M., Vittecoq, O. & Panayi, G. S. Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development. Immunology 128, 218-226 (2009).
104. Yang, Y. et al. Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26, 215-226 (2007).
105. Zhang, J. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518-522 (2006).
106. Luo, B. et al. The endoplasmic reticulum chaperone protein GRP94 is required for maintaining hematopoietic stem cell interactions with the adult bone marrow niche. PLoS ONE 6, e20364 (2011).
107. Luo, B., Tseng, C. C., Adams, G. B. & Lee, A. S. Deficiency of GRP94 in the hematopoietic system alters proliferation regulators in hematopoietic stem cells. Stem Cells Dev. 22, 3062-3073 (2013).
108. Wu, M. J. et al. Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling. Mol. Cancer 9, 283 (2010).
109. Chiu, C. C. et al. Grp78 as a therapeutic target for refractory head-neck cancer with CD24CD44 stemness phenotype. Cancer Gene Ther. 20, 606-615 (2013).
110. Galicia, V. A. et al. Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology 139, 2170-2182 (2010).
111. Chen, W. T. et al. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. Oncogene, http://dx.doi.org/10.1038/onc.2013.437 (2013).
112. Ji, C. et al. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54, 229-239 (2011).
113. Chen, W. T. et al. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. Hepatology, 59, 947-957 (2013).
114. Cook, K. L., Clarke, P. A. & Clarke, R. Targeting GRP78 and antiestrogen resistance in breast cancer. Future Med. Chem. 5, 1047-1057 (2013).
115. Gomer, C. J. et al. Photodynamic therapy-mediated oxidative stress can induce expression of heat shock proteins. Cancer Res. 56, 2355-2360 (1996).
116. Li, B., Cheng, X. L., Yang, Y. P. & Li, Z. Q. GRP78 mediates radiation resistance of a stem cell-like subpopulation within the MCF-7 breast cancer cell line. Oncol. Rep. 30, 2119-2126 (2013).
117. Roller, C. & Maddalo, D. The molecular chaperone GRP78/BiP in the development of chemoresistance: mechanism and possible treatment. Front. Pharmacol. 4, 10 (2013).
118. Kern, J. et al. GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood 114, 3960-3967 (2009).
119. Yang, L., Li, H., Jiang, Y., Zuo, J. & Liu, W. Inhibition of mortalin expression reverses cisplatin resistance and attenuates growth of ovarian cancer cells. Cancer Lett. 336, 213-221 (2013).
120. Thomas, S. et al. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I. PLoS ONE 8, e65695 (2013).
121. Su, S. F. et al. miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene 32, 4694-4701 (2013).
122. Dong, D. 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. 15, 553-561 (2004).
123. Azatian, A. et al. Effectiveness of HSV-tk suicide gene therapy driven by the Grp78 stress-inducible promoter in esophagogastric junction and gastric adenocarcinomas. J. Gastrointest. Surg. 13, 1044-1051 (2009).
124. Kia, A. et al. Dual systemic tumor targeting with ligand-directed phage and Grp78 promoter induces tumor regression. Mol. Cancer Ther. 11, 2566-2577 (2012).
125. Reddy, R. K. et al. Cancer-inducible transgene expression by the Grp94 promoter: spontaneous activation in tumors of various origins and cancer-Associated macrophages. Cancer Res. 62, 7207-7212 (2002).
126. Paton, A. W. et al. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 443, 548-552 (2006).
127. Backer, J. M. et al. Chaperone-targeting cytotoxin and endoplasmic reticulum stress-inducing drug synergize to kill cancer cells. Neoplasia 11, 1165-1173 (2009).
128. Prabhu, A., Sarcar, B., Kahali, S., Shan, Y. & Chinnaiyan, P. Targeting the unfolded protein response in glioblastoma cells with the fusion protein EGF-SubA. PLoS ONE 7, e52265 (2012).
129. Ermakova, S. P. et al. (-)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res. 66, 9260-9269 (2006).
130. Martin, S. et al. Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br. J. Cancer 109, 433-443 (2013).
131. Deng, W. G., Ruan, K. H., Du, M., Saunders, M. A. & Wu, K. K. Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts. FASEB J. 15, 2463-2470 (2001).
132. Maddalo, D. et al. A peptidic unconjugated GRP78/BiP ligand modulates the unfolded protein response and induces prostate cancer cell death. PLoS ONE 7, e45690 (2012).
133. Kahali, S. et al. Activation of the unfolded protein response contributes toward the antitumor activity of vorinostat. Neoplasia 12, 80-86 (2010).
134. Duerfeldt, A. S. et al. Development of a Grp94 inhibitor. J. Am. Chem. Soc. 134, 9796-9804 (2012).
135. Sheu, M. L., Liu, S. H. & Lan, K. H. Honokiol induces calpain-mediated glucose-regulated protein-94 cleavage and apoptosis in human gastric cancer cells and reduces tumor growth. PLoS ONE 2, e1096 (2007).
136. Han, J. M. et al. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoS ONE 5, e9792 (2010).
137. Kaul, S. C., Aida, S., Yaguchi, T., Kaur, K. & Wadhwa, R. Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J. Biol. Chem. 280, 39373-39379 (2005).
138. Wadhwa, R. et al. Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res. 60, 6818-6821 (2000).
139. Lu, W. J. et al. Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy. Cell Death Differ. 18, 1046-1056 (2011)
140. Utomo, D. H., Widodo, N. & Rifa'i, M. Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening. Bioinformation 8, 426-429 (2012).
141. Jakobsen, C. G., Rasmussen, N., Laenkholm, A. V. & Ditzel, H. J. Phage display derived human monoclonal antibodies isolated by binding to the surface of live primary breast cancer cells recognize GRP78. Cancer Res. 67, 9507-9517 (2007).
142. Arap, M. A. et al. Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands. Cancer Cell 6, 275-284 (2004).
143. Kim, Y. et al. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry 45, 9434-9444 (2006).
144. Liu, Y. et al. Mechanistic studies of a peptidic GRP78 ligand for cancer cell-specific drug delivery. Mol. Pharm. 4, 435-447 (2007).
145. Passarella, R. J. et al. Targeted nanoparticles that deliver a sustained, specific release of Paclitaxel to irradiated tumors. Cancer Res. 70, 4550-4559 (2010).
146. Larson, N., Ray, A., Malugin, A., Pike, D. B. & Ghandehari, H. HPMA copolymer-Aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer. Pharm. Res. 27, 2683-2693 (2010).
147. Uckun, F. M. et al. Inducing apoptosis in chemotherapy-resistant B-lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti-Apoptotic unfolded protein response signalling network. Br. J. Haematol. 153, 741-752 (2011).
148. Kang, J. et al. A peptide derived from phage display library exhibits anti-tumor activity by targeting GRP78 in gastric cancer multidrug resistance cells. Cancer Lett. 339, 247-259 (2013).
149. Delie, F., Petignat, P. & Cohen, M. GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78. Target Oncol. 8, 225-230 (2013).
150. Li, Z. et al. Reconstructed mung bean trypsin inhibitor targeting cell surface GRP78 induces apoptosis and inhibits tumor growth in colorectal cancer. Int. J. Biochem. Cell. Biol. 47, 68-75 (2014).
151. de Ridder, G. G., Ray, R. & Pizzo, S. V. A murine monoclonal antibody directed against the carboxyl-terminal domain of GRP78 suppresses melanoma growth in mice. Melanoma Res. 22, 225-235 (2012).
152. Rauschert, N. et al. A new tumor-specific variant of GRP78 as target for antibody-based therapy. Lab. Invest. 88, 375-386 (2008).
153. Rasche, L. et al. The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78. PLoS ONE 8, e63414 (2013).
154. Hensel, F., Eckstein, M., Rosenwald, A. & Brandlein, S. Early development of PAT-SM6 for the treatment of melanoma. Melanoma Res. 23, 264-275 (2013).
155. Cohen, M. & Petignat, P. Purified autoantibodies against glucose-regulated protein 78 (GRP78) promote apoptosis and decrease invasiveness of ovarian cancer cells. Cancer Lett. 309, 104-109 (2011).
156. Al-Hashimi, A. A. et al. Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores. J. Biol. Chem. 285, 28912-28923 (2010).
157. Arnouk, H. et al. Tumour secreted grp170 chaperones full-length protein substrates and induces an adaptive anti-tumour immune response in vivo. Int. J. Hyperthermia 26, 366-375 (2010).
158. Schreiber, T. H., Deyev, V. V., Rosenblatt, J. D. & Podack, E. R. Tumor-induced suppression of CTL expansion and subjugation by gp96-Ig vaccination. Cancer Res. 69, 2026-2033 (2009).
159. Randazzo, M., Terness, P., Opelz, G. & Kleist, C. Active-specific immunotherapy of human cancers with the heat shock protein Gp96-revisited. Int. J. Cancer 130, 2219-2231 (2012).
160. Reitsma, D. J. & Combest, A. J. Challenges in the development of an autologous heat shock protein based anti-tumor vaccine. Hum. Vaccin. Immunother. 8, 1152-1155 (2012).
161. Colaco, C. Autologous heat-shock protein vaccines. Hum. Vaccin. Immunother. 9, 275-276 (2013).
162. Li, X. et al. Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation. PLoS ONE 8, e68997 (2013).
163. Zhao, B. et al. TAT-mediated gp96 transduction to APCs enhances gp96-induced antiviral and antitumor T cell responses. Vaccine 31, 545-552 (2013).
164. Wang, X. Y. et al. Superior antitumor response induced by large stress protein chaperoned protein antigen compared with peptide antigen. J. Immunol. 184, 6309-6319 (2010).
165. Wang, X. Y. et al. Extracellular targeting of endoplasmic reticulum chaperone glucose-regulated protein 170 enhances tumor immunity to a poorly immunogenic melanoma. J. Immunol. 177, 1543-1551 (2006).
166. Gao, P., Sun, X., Chen, X., Subjeck, J. & Wang, X. Y. Secretion of stress protein grp170 promotes immune-mediated inhibition of murine prostate tumor. Cancer Immunol. Immunother. 58, 1319-1328 (2009).
167. Yu, X. et al. A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity. Cancer Res. 73, 2093-2103 (2013).
168. Tamura, Y. et al. Tumor-produced secreted form of binding of immunoglobulin protein elicits antigen-specific tumor immunity. J. Immunol. 186, 4325-4330 (2011).
169. Lee, A. S. in Protein Discovery Technologies (eds Pasqualini, R., & Arap, W.) 129-140 (CRC Press, 2009).
170. Pouyssegur, J., Shiu, R. P. & Pastan, I. Induction of two transformation-sensitive membrane polypeptides in normal fibroblasts by a block in glycoprotein synthesis or glucose deprivation. Cell 11, 941-947 (1977).
171. Hightower, L. E. Cultured animal cells exposed to amino acid analogues or puromycin rapidly synthesize several polypeptides. J. Cell. Physiol. 102, 407-427 (1980).
172. Munro, S. & Pelham, H. R. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46, 291-300 (1986).
173. Bole, D. G., Hendershot, L. M. & Kearney, J. F. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J. Cell Biol. 102, 1558-1566 (1986).
174. Haas, I. G. & Wabl, M. Immunoglobulin heavy chain binding protein. Nature 306, 387-389 (1983).
175. Hendershot, L. M. et al. In vivo expression of mammalian BiP ATPase mutants causes disruption of the endoplasmic reticulum. Mol. Biol. Cell 6, 283-296 (1995).
176. Lee, A. S., Bell, J. & Ting, J. Biochemical characterization of the 94-And 78-kilodalton glucose-regulated proteins in hamster fibroblasts. J. Biol. Chem. 259, 4616-4621 (1984).
177. Koch, G., Smith, M., Macer, D., Webster, P. & Mortara, R. Endoplasmic reticulum contains a common, abundant calcium-binding glycoprotein, endoplasmin. J. Cell Sci. 86, 217-232 (1986).
178. Mazzarella, R. A. & Green, M. ERp99, an abundant, conserved glycoprotein of the endoplasmic reticulum, is homologous to the 90-kDa heat shock protein (hsp90) and the 94-kDa glucose regulated protein (GRP94). J. Biol. Chem. 262, 8875-8883 (1987).
179. Maki, R. G., Old, L. J. & Srivastava, P. K. Human homologue of murine tumor rejection antigen gp96: 5?-regulatory and coding regions and relationship to stress-induced proteins. Proc. Natl Acad. Sci. USA 87, 5658-5662 (1990)
180. Johnson, J. L. Evolution and function of diverse Hsp90 homologs and cochaperone proteins. Biochim. Biophys. Acta 1823, 607-613 (2012).
181. Schild, H. & Rammensee, H. G. gp96-The immune system's Swiss army knife. Nature Immunol. 1, 100-101 (2000).
182. Wadhwa, R., Kaul, S. C., Ikawa, Y. & Sugimoto, Y. Identification of a novel member of mouse hsp70 family. Its association with cellular mortal phenotype. J. Biol. Chem. 268, 6615-6621 (1993).
183. Sciandra, J. J. & Subjeck, J. R. The effects of glucose on protein synthesis and thermosensitivity in Chinese hamster ovary cells. J. Biol. Chem. 258, 12091-12093 (1983).
184. Chen, X. et al. The 170 kDa glucose regulated stress protein is a large HSP70-, HSP110-like protein of the endoplasmic reticulum. FEBS Lett. 380, 68-72 (1996).
185. Kuwabara, K. et al. Purification and characterization of a novel stress protein, the 150-kDa oxygen-regulated protein (ORP150), from cultured rat astrocytes and its expression in ischemic mouse brain. J. Biol. Chem. 271, 5025-5032 (1996).
186. Sciandra, J. J., Subjeck, J. R. & Hughes, C. S. Induction of glucose-regulated proteins during anaerobic exposure and of heat-shock proteins after reoxygenation. Proc. Natl Acad. Sci. USA 81, 4843-4847 (1984).
187. Yoshida, H., Haze, K., Yanagi, H., Yura, T. & Mori, K. Identification of the cis-Acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem. 273, 33741-33749 (1998).
188. Roy, B. & Lee, A. S. The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res. 27, 1437-1443 (1999).
189. Baumeister, P. et al. Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers. Mol. Cell. Biol. 25, 4529-4540 (2005).
190. Hong, M. et al. Transcriptional regulation of the Grp78 promoter by endoplasmic reticulum stress: role of TFII-I and its tyrosine phosphorylation. J. Biol. Chem. 280, 16821-16828 (2005).
191. Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448-7459 (2003).
192. Kaneda, S., Yura, T. & Yanagi, H. Production of three distinct mRNAs of 150 kDa oxygen-regulated protein (ORP150) by alternative promoters: preferential induction of one species under stress conditions. J. Biochem. 128, 529-538 (2000).
193. Giorgi, C., De Stefani, D., Bononi, A., Rizzuto, R. & Pinton, P. Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int. J. Biochem. Cell. Biol. 41, 1817-1827 (2009).
194. Hayashi, T., Rizzuto, R., Hajnoczky, G. & Su, T. P. MAM: more than just a housekeeper. Trends Cell Biol. 19, 81-88 (2009).
195. Hetz, C. A. ER stress signaling and the BCL-2 family of proteins: from adaptation to irreversible cellular damage. Antioxid. Redox Signal. 9, 2345-2355 (2007).
196. 2+ handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11, 279-286 (2011).
197. Sun, F. C. et al. Localization of GRP78 to mitochondria under the unfolded protein response. Biochem. J. 396, 31-39 (2006).
198. Ye, R. et al. Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance. Diabetes 59, 6-16 (2010).
199. Mao, C. et al. Targeted mutation of the mouse Grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling. PLoS ONE 5, e10852 (2010).