title: The Endoplasmic Reticulum Chaperone GRP170: From Immunobiology to Cancer Therapeutics.
abstract: Glucose-regulated protein 170 (GRP170) is the largest member of glucose-regulated protein family that resides in the endoplasmic reticulum (ER). As a component of the ER chaperone network, GRP170 assists in protein folding, assembly, and transportation of secretory or transmembrane proteins. The well documented cytoprotective activity of intracellular GRP170 due to its intrinsic chaperoning property has been shown to provide a survival benefit in cancer cells during tumor progression or metastasis. Accumulating evidence shows that extracellular GRP170 displays a superior capacity in delivering tumor antigens to specialized antigen-presenting cells for cross-presentation, resulting in generation of an anti-tumor immune response dependent on cytotoxic CD8(+) T cells. This unique feature of GRP170 provides a molecular basis for using GRP170 as an immunostimulatory adjuvant to develop a recombinant vaccine for therapeutic immunization against cancers. This review summarizes the latest findings in understanding the biological effects of GRP170 on cell functions and tumor progression. The immunomodulating activities of GRP170 during interactions with the innate and adaptive arms of the immune system as well as its therapeutic applications in cancer immunotherapy will be discussed.
authors: Department of Human Molecular Genetics, Virginia Commonwealth University , Richmond, VA , USA.
authors: Hongxia
authors: H
authors: Wang
authors: Department of Human Molecular Genetics, Virginia Commonwealth University , Richmond, VA , USA.
authors: Abdul Mohammad
authors: AM
authors: Pezeshki
authors: Department of Human Molecular Genetics, Virginia Commonwealth University , Richmond, VA , USA.
authors: Xiaofei
authors: X
authors: Yu
authors: Department of Human Molecular Genetics, Virginia Commonwealth University , Richmond, VA , USA.
authors: Chunqing
authors: C
authors: Guo
authors: Department of Cell Stress Biology, Roswell Park Cancer Institute , Buffalo, NY , USA.
authors: John R
authors: JR
authors: Subjeck
authors: Department of Human Molecular Genetics, Virginia Commonwealth University , Richmond, VA , USA ; Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA ; Institute of Molecular Medicine, Virginia Commonwealth University , Richmond, VA , USA.
authors: Xiang-Yang
authors: XY
authors: Wang
keywords: anti-tumor immunity; cancer vaccine; endoplasmic reticulum; glucose-regulated protein 170; molecular chaperone
references: Immunol Rev. 2004 Jun;199:9-26
references: 15233723
references: Mol Biol Cell. 1993 Nov;4(11):1109-19
references: 8305733
references: Front Immunol. 2012 Mar 30;3:63
references: 22566944
references: Curr Mol Med. 2006 Feb;6(1):55-69
references: 16472113
references: Mol Biol Cell. 2010 May 1;21(9):1439-48
references: 20237159
references: Nat Rev Cancer. 2014 Apr;14(4):263-76
references: 24658275
references: Nat Immunol. 2008 May;9(5):551-7
references: 18376401
references: J Biochem. 2000 Sep;128(3):529-38
references: 10965054
references: Ann N Y Acad Sci. 2010 Oct;1209:77-82
references: 20958319
references: Breast Cancer Res Treat. 2000 Jan;59(1):15-26
references: 10752676
references: Nature. 2003 Sep 25;425(6956):402-6
references: 14508490
references: Cell Death Differ. 2008 Aug;15(8):1255-65
references: 18404158
references: Methods. 2004 Jan;32(1):63-9
references: 14624879
references: Cell Stress Chaperones. 2000 Oct;5(4):276-90
references: 11048651
references: Cancer Immunol Immunother. 2009 Aug;58(8):1319-28
references: 19142636
references: J Biol Chem. 1983 Oct 25;258(20):12091-3
references: 6630181
references: BJU Int. 2002 Sep;90(4):462-6
references: 12175409
references: J Immunol. 2006 Dec 1;177(11):7849-57
references: 17114456
references: J Immunol. 2008 Jul 1;181(1):354-63
references: 18566401
references: Ann N Y Acad Sci. 2007 Oct;1113:28-39
references: 17978280
references: J Immunol. 2010 Jun 1;184(11):6309-19
references: 20439916
references: J Cell Biol. 2010 May 31;189(5):783-94
references: 20513765
references: Nature. 2003 Sep 25;425(6956):397-402
references: 14508489
references: FASEB J. 2013 Mar;27(3):955-64
references: 23180827
references: Proc Natl Acad Sci U S A. 1984 Aug;81(15):4843-7
references: 6589630
references: Immunol Rev. 2005 Oct;207:145-57
references: 16181333
references: Med Sci Monit. 2007 Nov;13(11):BR231-239
references: 17968289
references: EMBO J. 2000 Dec 1;19(23):6440-52
references: 11101517
references: Immunity. 2004 Aug;21(2):155-65
references: 15308097
references: Cancer Res. 2013 Apr 1;73(7):2093-103
references: 23333935
references: Nat Cell Biol. 1999 Oct;1(6):362-8
references: 10559964
references: Immunity. 2010 Oct 29;33(4):492-503
references: 21029960
references: J Immunol. 2007 Aug 15;179(4):2310-7
references: 17675492
references: J Biol Chem. 2014 Jan 31;289(5):2899-907
references: 24327659
references: Trends Cell Biol. 2004 Jan;14(1):20-8
references: 14729177
references: Curr Opin Cell Biol. 2013 Aug;25(4):428-33
references: 23478217
references: J Exp Med. 1995 Sep 1;182(3):885-9
references: 7650492
references: Nat Immunol. 2009 May;10(5):488-95
references: 19349986
references: J Immunol. 2001 Jan 1;166(1):490-7
references: 11123328
references: J Immunol. 2006 Aug 1;177(3):1543-51
references: 16849461
references: Cold Spring Harb Perspect Biol. 2011 Nov 01;3(11):a007526
references: 21875985
references: J Immunol. 1999 Jun 1;162(11):6426-32
references: 10352256
references: Lab Invest. 1998 Jun;78(6):699-706
references: 9645760
references: Immunol Cell Biol. 2006 Apr;84(2):203-8
references: 16519738
references: Cancer Res. 2001 May 15;61(10):4206-13
references: 11358846
references: J Clin Endocrinol Metab. 2010 Nov;95(11):E319-26
references: 20719828
references: Vaccine. 2010 Aug 31;28(38):6333-7
references: 20637304
references: J Clin Invest. 2001 Nov;108(10):1439-50
references: 11714735
references: Science. 1997 Oct 3;278(5335):117-20
references: 9311915
references: Biochemistry. 2003 Dec 23;42(50):14893-902
references: 14674765
references: Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7690-4
references: 8755537
references: Cancer Immun. 2003 Jan 28;3:1
references: 12747743
references: J Biol Chem. 1997 Dec 12;272(50):31636-40
references: 9395504
references: Annu Rev Immunol. 2002;20:395-425
references: 11861608
references: Trends Biochem Sci. 2006 Mar;31(3):164-72
references: 16483782
references: Mol Cancer Res. 2005 Nov;3(11):597-605
references: 16317085
references: Nature. 2006 Apr 6;440(7085):808-12
references: 16489357
references: Int Immunol. 2000 Nov;12(11):1539-46
references: 11058573
references: Handb Exp Pharmacol. 2006;(172):305-29
references: 16610365
references: Trends Cell Biol. 1997 Jul;7(7):277-82
references: 17708960
references: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):5987-93
references: 17062670
references: J Cell Physiol. 1981 Jan;106(1):119-25
references: 7204505
references: J Biol Chem. 1998 Dec 11;273(50):33741-9
references: 9837962
references: FASEB J. 2003 May;17(8):923-5
references: 12670879
references: Acta Med Okayama. 2012;66(1):1-6
references: 22358133
references: Eur J Immunol. 2007 Aug;37(8):2268-79
references: 17615582
references: FEBS Lett. 2006 Oct 2;580(22):5237-40
references: 16962589
references: J Immunol. 2009 Nov 1;183(9):5861-9
references: 19812200
references: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14459-64
references: 16971487
references: Nat Rev Mol Cell Biol. 2010 Aug;11(8):579-92
references: 20651708
references: Cell Stress Chaperones. 2010 Mar;15(2):123-41
references: 19731087
references: J Leukoc Biol. 2007 Jan;81(1):15-27
references: 16931602
references: Biochim Biophys Acta. 2013 Nov;1833(11):2410-24
references: 23507200
references: Brain Res. 2004 Jul 23;1015(1-2):122-8
references: 15223375
references: Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a013169
references: 23388626
references: Mol Pharmacol. 2007 Mar;71(3):860-70
references: 17167033
references: Curr Pharm Des. 2013;19(15):2807-18
references: 23363441
references: FASEB J. 2012 Apr;26(4):1493-505
references: 22207611
references: Nature. 2001 Apr 26;410(6832):1099-103
references: 11323673
references: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6561-6
references: 21464300
references: Cell Stress Chaperones. 2007 Spring;12(1):1-8
references: 17441502
references: Cancer Res. 2006 Jan 15;66(2):1161-8
references: 16424054
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15824-9
references: 14668429
references: Biomed Res Int. 2013;2013:461230
references: 23762847
references: Cell. 2002 Jul 12;110(1):119-31
references: 12151002
references: Science. 2008 Nov 14;322(5904):1097-100
references: 19008445
references: Nat Rev Mol Cell Biol. 2012 Jan 18;13(2):89-102
references: 22251901
references: Expert Rev Vaccines. 2004 Aug;3(4):403-11
references: 15270645
references: Trends Biochem Sci. 2001 Aug;26(8):504-10
references: 11504627
references: J Biol Chem. 2013 Jun 21;288(25):18366-80
references: 23645669
references: Proc Natl Acad Sci U S A. 1986 May;83(10):3407-11
references: 3458189
references: J Immunol. 2013 Dec 15;191(12 ):6010-21
references: 24218449
references: Science. 1995 Jan 13;267(5195):243-6
references: 7809629
references: J Cell Physiol. 1993 Feb;154(2):229-37
references: 8425905
references: Nat Rev Immunol. 2012 Jul 13;12(8):557-69
references: 22790179
references: PLoS One. 2013 Nov 11;8(11):e80071
references: 24244613
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Mutat Res. 2005 Jan 6;569(1-2):29-63
references: 15603751
references: Cancer Res. 2007 Sep 1;67(17):7941-4
references: 17804698
references: Nat Rev Drug Discov. 2008 Dec;7(12 ):1013-30
references: 19043451
references: PLoS One. 2012;7(12):e51735
references: 23272152
references: J Immunol. 2011 Apr 1;186(7):4325-30
references: 21339366
references: J Clin Invest. 2005 Oct;115(10 ):2656-64
references: 16200199
references: Int J Radiat Biol. 2005 Sep;81(9):701-9
references: 16368648
references: J Clin Invest. 2005 Mar;115(3):739-46
references: 15696196
references: Immunity. 2007 Feb;26(2):215-26
references: 17275357
references: Eur J Immunol. 2005 Sep;35(9):2518-27
references: 16144035
references: J Immunol. 2007 Mar 1;178(5):3219-25
references: 17312170
references: J Biol Chem. 1996 Mar 1;271(9):5025-32
references: 8617779
references: Science. 2012 Feb 17;335(6070):859-64
references: 22344444
references: J Biol Chem. 2004 Feb 13;279(7):5667-75
references: 14634022
references: Proc Natl Acad Sci U S A. 1987 May;84(10):3278-82
references: 3106964
references: Philos Trans R Soc Lond B Biol Sci. 2011 Oct 12;366(1579):2748-55
references: 21893536
references: Cell Death Differ. 2010 Mar;17(3):488-98
references: 19816510
references: EMBO J. 1996 Dec 16;15(24):6931-42
references: 9003769
references: Biochemistry. 1999 Aug 10;38(32):10559-66
references: 10441153
references: J Exp Med. 2007 Oct 1;204(10 ):2267-75
references: 17875675
references: Eur J Immunol. 2007 May;37(5):1184-93
references: 17407099
references: Hum Pathol. 2007 Oct;38(10):1547-52
references: 17640713
references: J Cell Physiol. 1985 Nov;125(2):251-8
references: 4055909
references: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6135-9
references: 8650232
references: Mol Cancer. 2004 Aug 06;3:21
references: 15298707
references: Nature. 1994 Aug 4;370(6488):373-5
references: 7913987
references: J Biol Chem. 2009 Nov 13;284(46):31564-71
references: 19759005
references: Cancer Res. 2003 May 15;63(10):2553-60
references: 12750279
references: Nat Med. 2001 Mar;7(3):317-23
references: 11231630
references: Immunity. 2003 Mar;18(3):381-90
references: 12648455
references: Science. 2011 Nov 25;334(6059):1086-90
references: 22116878
references: J Hematol Oncol. 2011 Feb 23;4:8
references: 21345215
references: J Biol Chem. 2010 Apr 16;285(16):12445-53
references: 20177057
references: Immunity. 2006 Oct;25(4):607-17
references: 17027300
references: Circ Res. 2009 Feb 13;104(3):328-36
references: 19106412
references: Biomed Res Int. 2014;2014:196249
references: 24605321
references: J Mol Cell Cardiol. 2005 Mar;38(3):517-25
references: 15733911
references: Immunity. 1998 Jun;8(6):657-65
references: 9655479
references: FEBS Lett. 1996 Feb 12;380(1-2):68-72
references: 8603749
references: Nat Rev Immunol. 2004 Jul;4(7):499-511
references: 15229469
references: Immunol Lett. 2012 Sep;147(1-2):55-62
references: 22732235
references: EMBO J. 1996 Jun 3;15(11):2640-50
references: 8654361
references: Proc Natl Acad Sci U S A. 1981 Aug;78(8):4922-5
references: 6946438
references: Int Immunol. 2001 May;13(5):675-83
references: 11312255
references: Curr Opin Immunol. 2014 Feb;26:63-8
references: 24556402
references: Genes Cells. 2004 May;9(5):457-69
references: 15147274
references: Cancer Res. 2006 Aug 15;66(16):7849-53
references: 16912156
references: Expert Opin Biol Ther. 2009 Feb;9(2):179-86
references: 19236248
references: Int J Cancer. 2003 Jun 10;105(2):226-31
references: 12673684
references: Nat Rev Immunol. 2002 Mar;2(3):185-94
references: 11913069
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10326-31
references: 10468607
references: Biochem Biophys Res Commun. 1997 Jan 3;230(1):94-9
references: 9020069
references: J Immunol. 1999 Nov 15;163(10):5178-82
references: 10553037
references: Clin Cancer Res. 2013 Dec 15;19(24):6802-11
references: 24048331
references: Cell. 2000 Apr 28;101(3):249-58
references: 10847680
references: J Biol Chem. 2010 May 14;285(20):15065-75
references: 20208072
references: Int J Hyperthermia. 2013 Aug;29(5):364-75
references: 23829534
references: J Biol Chem. 2011 Apr 1;286(13):11119-31
references: 21296878
references: Ann Surg Oncol. 2009 Feb;16(2):524-33
references: 19050968
references: Trends Immunol. 2006 Jan;27(1):49-55
references: 16310411
references: Nat Rev Mol Cell Biol. 2002 Apr;3(4):246-55
references: 11994744
references: Immunobiology. 2012 Jul;217(7):738-42
references: 22317751
references: Int J Hyperthermia. 2010;26(4):366-75
references: 20210603
references: Blood. 2003 Jan 1;101(1):245-52
references: 12393411
references: Oncogene. 2013 Feb 14;32(7):805-18
references: 22508478
references: J Biol Chem. 2002 Nov 1;277(44):42082-7
references: 12194978
references: Int J Pharm. 2014 May 15;466(1-2):139-46
references: 24607202
references: Leuk Res. 2009 Jul;33(7):880-2
references: 19285722
references: J Biol Chem. 1999 Mar 5;274(10):6397-404
references: 10037731
references: Science. 2011 Nov 25;334(6059):1081-6
references: 22116877
references: Nat Rev Mol Cell Biol. 2008 Dec;9(12):944-57
references: 19002207
references: Cell. 2009 Aug 7;138(3):562-75
references: 19665977
references: Int J Hyperthermia. 2008 Feb;24(1):31-9
references: 18214767
references: J Immunol. 2007 Feb 1;178(3):1301-11
references: 17237376
references: J Immunol. 2003 Oct 1;171(7):3467-74
references: 14500642
references: J Immunol. 2008 Oct 15;181(8):5433-41
references: 18832700
references: Cancer Res. 2008 May 15;68(10):3890-8
references: 18483274
references: Nature. 1993 Jan 28;361(6410):359-62
references: 7678924
references: PLoS One. 2012;7(6):e39047
references: 22723926
references: Int J Urol. 2002 Oct;9(10):577-85
references: 12445237
references: Neurochem Res. 2013 Apr;38(4):686-93
references: 23325452
references: Nat Immunol. 2014 Mar;15(3):248-57
references: 24441789
references: Mol Cell Biol. 2006 Aug;26(15):5688-97
references: 16847323
references: Nat Med. 2010 Apr;16(4):396-9
references: 20376052
references: Cell Death Differ. 2007 Oct;14(10):1848-50
references: 17657249
references: Nature. 2011 Jul 20;475(7356):324-32
references: 21776078
references: J Biol Chem. 1999 Oct 1;274(40):28476-83
references: 10497210
references: Cancer Biol Ther. 2006 Jul;5(7):741-4
references: 16861902