title: αB-crystallin: Portrait of a malignant chaperone as a cancer therapeutic target.
abstract: αB-crystallin is a widely expressed member of the small heat shock protein family that protects cells from stress by its dual function as a molecular chaperone to preserve proteostasis and as a cell death antagonist that negatively regulates components of the conserved apoptotic cell death machinery. Deregulated expression of αB-crystallin occurs in a broad array of solid tumors and has been linked to tumor progression and poor clinical outcomes. This review will focus on new insights into the molecular mechanisms by which oncogenes, oxidative stress, matrix detachment and other tumor microenvironmental stressors deregulate αB-crystallin expression. We will also review accumulating evidence pointing to an essential role for αB-crystallin in the multi-step metastatic cascade whereby tumor cells colonize distant organs by circumventing a multitude of barriers to cell migration and survival. Finally, we will evaluate emerging strategies to therapeutically target αB-crystallin and/or interacting proteins to selectively activate apoptosis and/or derail the metastatic cascade in an effort to improve outcomes for patients with metastatic disease.
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Malin
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Petrovic
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Strekalova
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Bhawna
authors.initials: B
authors.lastname: Sharma
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address: vlcryns@medicine.wisc.edu.
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
mesh_terms: D017209:Apoptosis / Q000502:physiology; D003459:Crystallins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D003459:Crystallins; D018832:Molecular Chaperones
keywords: Apoptosis; Cancer; Drug target; Metastasis; Molecular chaperone; Stress response
references.citation: Exp Cell Res. 1999 Dec 15;253(2):649-62
references.pmid: 10585288
references.citation: J Biol Chem. 2000 Jan 14;275(2):1095-104
references.pmid: 10625651
references.citation: Nature. 2000 Aug 17;406(6797):747-52
references.pmid: 10963602
references.citation: J Biol Chem. 2000 Nov 24;275(47):36823-31
references.pmid: 10967101
references.citation: J Natl Cancer Inst. 2000 Oct 4;92(19):1564-72
references.pmid: 11018092
references.citation: J Biol Chem. 2001 Feb 16;276(7):5346-52
references.pmid: 11096101
references.citation: J Biol Chem. 2001 May 11;276(19):16059-63
references.pmid: 11274139
references.citation: J Biochem. 2001 May;129(5):813-20
references.pmid: 11328606
references.citation: Curr Opin Cell Biol. 2001 Oct;13(5):555-62
references.pmid: 11544023
references.citation: J Biol Chem. 2001 Nov 16;276(46):43435-45
references.pmid: 11546795
references.citation: J Biol Chem. 2002 Oct 11;277(41):38731-6
references.pmid: 12140279
references.citation: J Biol Chem. 2002 Nov 29;277(48):46310-8
references.pmid: 12297515
references.citation: Nat Cell Biol. 2002 Nov;4(11):859-64
references.pmid: 12389032
references.citation: J Biol Chem. 2002 Dec 20;277(51):49700-6
references.pmid: 12403771
references.citation: Cancer Res. 2002 Nov 15;62(22):6740-9
references.pmid: 12438275
references.citation: J Biol Chem. 2003 Mar 21;278(12):10361-7
references.pmid: 12529319
references.citation: Circ Res. 2003 Feb 7;92(2):203-11
references.pmid: 12574148
references.citation: Biochem Biophys Res Commun. 2003 Nov 7;311(1):162-7
references.pmid: 14575708
references.citation: Cancer Res. 2003 Dec 15;63(24):8648-55
references.pmid: 14695176
references.citation: Cell Death Differ. 2004 May;11(5):512-26
references.pmid: 14752512
references.citation: Science. 2004 Feb 13;303(5660):1010-4
references.pmid: 14963330
references.citation: Mol Carcinog. 2004 May;40(1):47-61
references.pmid: 15108329
references.citation: Cancer. 2004 Jun 15;100(12):2543-8
references.pmid: 15197794
references.citation: J Biol Chem. 2005 Mar 25;280(12):11059-66
references.pmid: 15653686
references.citation: J Mol Evol. 2004 Nov;59(5):674-86
references.pmid: 15693623
references.citation: Exp Cell Res. 2005 May 15;306(1):203-15
references.pmid: 15878345
references.citation: Laryngoscope. 2005 Jul;115(7):1239-42
references.pmid: 15995513
references.citation: Cell Stress Chaperones. 2005 Autumn;10(3):171-84
references.pmid: 16184762
references.citation: J Clin Invest. 2006 Jan;116(1):261-70
references.pmid: 16395408
references.citation: Biochemistry. 2006 Mar 7;45(9):3069-76
references.pmid: 16503662
references.citation: Nat Rev Cancer. 2006 Jun;6(6):449-58
references.pmid: 16723991
references.citation: Histopathology. 2006 Jul;49(1):10-21
references.pmid: 16842242
references.citation: Biochem J. 2007 Jan 1;401(1):129-41
references.pmid: 16928191
references.citation: Trends Mol Med. 2006 Nov;12(11):537-44
references.pmid: 17011236
references.citation: Genes Dev. 2007 Jan 1;21(1):98-111
references.pmid: 17210792
references.citation: Biochem Biophys Res Commun. 2007 Mar 2;354(1):109-14
references.pmid: 17222797
references.citation: FEBS Lett. 2007 Jul 31;581(19):3665-74
references.pmid: 17467701
references.citation: Biochemistry. 2007 May 29;46(21):6308-17
references.pmid: 17487982
references.citation: PLoS One. 2007 Jun 06;2(6):e498
references.pmid: 17551579
references.citation: Cell. 2007 Sep 21;130(6):1005-18
references.pmid: 17889646
references.citation: Breast Cancer Res Treat. 2008 Oct;111(3):411-7
references.pmid: 17968656
references.citation: Blood. 2008 Feb 15;111(4):2015-23
references.pmid: 18063749
references.citation: Ann Diagn Pathol. 2008 Feb;12(1):33-40
references.pmid: 18164413
references.citation: Biochem Soc Trans. 2008 Feb;36(Pt 1):1-9
references.pmid: 18208375
references.citation: Neurosci Lett. 2008 Apr 18;435(2):131-6
references.pmid: 18343576
references.citation: Cancer Treat Rev. 2008 Jun;34(4):378-90
references.pmid: 18367336
references.citation: Cancer Res. 2008 May 1;68(9):3108-14
references.pmid: 18451135
references.citation: N Engl J Med. 2008 May 8;358(19):2039-49
references.pmid: 18463380
references.citation: Pathology. 2008 Aug;40(5):500-4
references.pmid: 18604737
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10703-8
references.pmid: 18669646
references.citation: J Biol Chem. 2008 Oct 17;283(42):28513-7
references.pmid: 18713743
references.citation: Breast Cancer Res Treat. 2010 Jan;119(1):63-70
references.pmid: 19205872
references.citation: Nat Rev Cancer. 2009 Apr;9(4):274-84
references.pmid: 19308067
references.citation: Biochemistry. 2009 May 12;48(18):3828-37
references.pmid: 19323523
references.citation: Expert Opin Ther Targets. 2009 Apr;13(4):469-78
references.pmid: 19335068
references.citation: J Cell Biochem. 2009 Jun 1;107(3):504-15
references.pmid: 19343786
references.citation: J Mol Biol. 2009 Oct 9;392(5):1242-52
references.pmid: 19646995
references.citation: Eur J Cardiothorac Surg. 2010 Jan;37(1):44-50
references.pmid: 19651521
references.citation: Breast Cancer Res Treat. 2010 Jul;122(1):159-68
references.pmid: 19777343
references.citation: Cancer Sci. 2009 Dec;100(12):2368-75
references.pmid: 19799611
references.citation: Blood. 2010 Apr 22;115(16):3398-406
references.pmid: 20023214
references.citation: Protein Sci. 2010 May;19(5):1031-43
references.pmid: 20440841
references.citation: J Clin Oncol. 2010 Jul 10;28(20):3271-7
references.pmid: 20498394
references.citation: Nat Struct Mol Biol. 2010 Sep;17(9):1037-42
references.pmid: 20802487
references.citation: Am J Pathol. 2010 Oct;177(4):1618-28
references.pmid: 20813964
references.citation: J Biol Chem. 2010 Nov 26;285(48):37324-32
references.pmid: 20841355
references.citation: Mol Endocrinol. 2011 Feb;25(2):199-211
references.pmid: 20861225
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6409-14
references.pmid: 21464278
references.citation: J Comp Pathol. 2012 Feb-Apr;146(2-3):143-51
references.pmid: 21783201
references.citation: Mol Biol Cell. 2011 Oct;22(19):3571-83
references.pmid: 21813737
references.citation: J Breast Cancer. 2011 Mar;14(1):14-9
references.pmid: 21847389
references.citation: Histopathology. 2011 Aug;59(2):247-55
references.pmid: 21884203
references.citation: J Cell Sci. 2011 Oct 1;124(Pt 19):3189-97
references.pmid: 21940791
references.citation: Mol Cancer Res. 2011 Dec;9(12):1632-43
references.pmid: 21984182
references.citation: Cell Stress Chaperones. 2012 Mar;17(2):157-69
references.pmid: 22002549
references.citation: Urol Oncol. 2013 Oct;31(7):1367-77
references.pmid: 22417627
references.citation: Histopathology. 2012 Sep;61(3):378-86
references.pmid: 22463677
references.citation: Free Radic Biol Med. 2012 Sep 1;53(5):1111-22
references.pmid: 22781655
references.citation: Cell. 2012 Aug 3;150(3):549-62
references.pmid: 22863008
references.citation: Tumour Biol. 2012 Dec;33(6):2279-88
references.pmid: 22972503
references.citation: Neuro Oncol. 2012 Nov;14(11):1332-45
references.pmid: 23074197
references.citation: Int J Cancer. 2013 Jun 15;132(12):2820-32
references.pmid: 23225306
references.citation: J Exp Clin Cancer Res. 2012 Dec 12;31:101
references.pmid: 23231769
references.citation: Hepatology. 2013 Jun;57(6):2235-47
references.pmid: 23316005
references.citation: FEBS Lett. 2013 Apr 17;587(8):1073-80
references.pmid: 23340341
references.citation: PLoS One. 2013;8(2):e55372
references.pmid: 23383327
references.citation: Breast Cancer Res Treat. 2013 Apr;138(2):415-25
references.pmid: 23471649
references.citation: BMC Cancer. 2013 Mar 18;13:128
references.pmid: 23506259
references.citation: J Biol Chem. 2013 May 10;288(19):13602-9
references.pmid: 23532854
references.citation: Mol Cell Biochem. 2013 Jul;379(1-2):59-68
references.pmid: 23543138
references.citation: Clin Genet. 2014 Apr;85(4):381-5
references.pmid: 23590293
references.citation: Int J Biol Markers. 2013 Dec 17;28(4):e365-70
references.pmid: 23722303
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):E3780-9
references.pmid: 24043785
references.citation: Oncogene. 2014 Aug 21;33(34):4352-8
references.pmid: 24077282
references.citation: Biochemistry. 2013 Nov 12;52(45):8126-38
references.pmid: 24128140
references.citation: Clin Cancer Res. 2014 Jan 1;20(1):56-67
references.pmid: 24132917
references.citation: Curr Drug Targets. 2014 Apr;15(4):423-31
references.pmid: 24138636
references.citation: Nat Med. 2013 Nov;19(11):1438-49
references.pmid: 24202396
references.citation: J Pathol. 2014 Mar;232(4):458-72
references.pmid: 24307592
references.citation: J Neurooncol. 2014 Mar;117(1):53-65
references.pmid: 24473683
references.citation: Prog Biophys Mol Biol. 2014 Jul;115(1):3-10
references.pmid: 24576798
references.citation: Prog Biophys Mol Biol. 2014 Jul;115(1):11-20
references.pmid: 24674783
references.citation: Breast Cancer Res Treat. 2014 May;145(1):45-59
references.pmid: 24710637
references.citation: BMC Cancer. 2014 Apr 11;14:252
references.pmid: 24725344
references.citation: Head Neck. 2015 Sep;37(9):1344-8
references.pmid: 24817638
references.citation: Biochim Biophys Acta. 2014 Jul;1839(7):592-603
references.pmid: 24859470
references.citation: J Surg Res. 2014 Aug;190(2):565-74
references.pmid: 24880201
references.citation: Trends Cell Biol. 2014 Aug;24(8):472-8
references.pmid: 24985940
references.citation: BMC Clin Pathol. 2014 Jun 23;14:28
references.pmid: 24987308
references.citation: Prog Retin Eye Res. 2014 Sep;42:145-61
references.pmid: 24998680
references.citation: Med Oncol. 2014 Aug;31(8):142
references.pmid: 25048725
references.citation: Nat Commun. 2014 Oct 16;5:5159
references.pmid: 25319025
references.citation: Int J Clin Exp Pathol. 2014 Aug 15;7(9):6056-63
references.pmid: 25337251
references.citation: Cell Mol Life Sci. 2015 Feb;72(3):429-451
references.pmid: 25352169
references.citation: Biochim Biophys Acta. 2015 Apr;1854(4):291-319
references.pmid: 25556000
references.citation: J Mol Biol. 2015 Apr 10;427(7):1537-48
references.pmid: 25681016
references.citation: Oncogene. 2015 Nov 5;34(45):5626-34
references.pmid: 25684139
references.citation: Biochim Biophys Acta. 2016 Jan;1860(1 Pt B):252-7
references.pmid: 25840354
references.citation: Genomics. 1989 Nov;5(4):665-9
references.pmid: 2591958
references.citation: Free Radic Biol Med. 2015 Sep;86:331-42
references.pmid: 26066304
references.citation: Biochim Biophys Acta. 2016 Jan;1860(1 Pt B):149-66
references.pmid: 26116912
references.citation: Cancer J. 2015 Jul-Aug;21(4):267-73
references.pmid: 26222078
references.citation: NPJ Breast Cancer. 2015 Oct 21;1:null
references.pmid: 27656679
references.citation: Int J Cancer. 1993 Nov 11;55(5):760-4
references.pmid: 8244572
references.citation: Mamm Genome. 1993;4(2):104-8
references.pmid: 8431633
references.citation: Am J Physiol. 1996 Mar;270(3 Pt 1):C903-9
references.pmid: 8638673
references.citation: EMBO J. 1996 Jun 3;15(11):2695-706
references.pmid: 8654367
references.citation: EMBO J. 1997 Jan 15;16(2):221-9
references.pmid: 9029143
references.citation: J Cell Sci. 1997 Nov;110 ( Pt 21):2759-69
references.pmid: 9427392
references.citation: Genes Dev. 1998 Jun 1;12(11):1551-70
references.pmid: 9620844