title: Versican G3 domain modulates breast cancer cell apoptosis: a mechanism for breast cancer cell response to chemotherapy and EGFR therapy.
abstract: Overexpression of EGFR and versican has been reported in association with breast cancers. Considered oncogenic, these molecules may be attractive therapeutic targets. Possessing anti-apoptotic and drug resistant properties, overexpression of these molecules is accompanied by selective sensitization to the process of apoptosis. In this study, we exogenously expressed a versican G3 construct in breast cancer cell lines and analyzed the effects of G3 on cell viability in fetal bovine serum free conditioned media and evaluated the effects of apoptotic agent C2-ceramide, and chemotherapeutic agents including Docetaxel, Doxorubicin, and Epirubicin. Versican G3 domain enhanced tumor cell resistance to apoptosis when cultured in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P). However, it could be prevented by selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059. Both AG 1478 and PD 98059 enhanced expression of pSAPK/JNK, while selective JNK inhibitor SP 600125 enhanced expression of GSK-3β (S9P). Versican G3 promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhancing expression of pSAPK/JNK and decreasing expression of GSK-3β (S9P), an observation blocked by AG 1478 or SP 6000125. Inhibition of endogenous versican expression by siRNA or reduction of versican G3's expression by linking G3 with 3'UTR prevented G3 modulated cell apoptosis. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents may in part explain a potential mechanism for breast cancer cell resistance to chemotherapy and EGFR therapy. The apoptotic effects of chemotherapeutics depend upon the activation and balance of down stream signals in the EGFR pathway. GSK-3β (S9P) appears to function as a key checkpoint in this balance of apoptosis and anti-apoptosis. Investigation and potential consideration of targeting GSK-3β (S9P) merits further study.
authors.affiliation: Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
authors.forename: William Weidong
authors.initials: WW
authors.lastname: Du
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.forename: Bing L
authors.initials: BL
authors.lastname: Yang
authors.forename: Zhaoqun
authors.initials: Z
authors.lastname: Deng
authors.forename: Ling
authors.initials: L
authors.lastname: Fang
authors.forename: Sze Wan
authors.initials: SW
authors.lastname: Shan
authors.forename: Zina
authors.initials: Z
authors.lastname: Jeyapalan
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Arun
authors.initials: A
authors.lastname: Seth
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Yee
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D053675:Versicans / Q000235:genetics / Q000378:metabolism*
chemical_list: D000873:Anthracenes; C064769:N-acetylsphingosine; D011799:Quinazolines; D043823:Taxoids; D020032:Tyrphostins; C485184:enhanced green fluorescent protein; D053675:Versicans; D049452:Green Fluorescent Proteins; D000077143:Docetaxel; C101044:RTKI cpd; C432165:pyrazolanthrone; D015251:Epirubicin; D004317:Doxorubicin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D013110:Sphingosine
references.citation: Nat Rev Cancer. 2004 Dec;4(12):937-47
references.pmid: 15573115
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20350-5
references.pmid: 18077375
references.citation: Cell. 1995 Jan 27;80(2):179-85
references.pmid: 7834738
references.citation: Cancer. 1996 Aug 1;78(3):542-7
references.pmid: 8697402
references.citation: Cancer Res. 2007 May 15;67(10):4742-50
references.pmid: 17510402
references.citation: Clin Cancer Res. 2004 Apr 1;10(7):2491-8
references.pmid: 15073129
references.citation: PLoS One. 2009 Sep 29;4(9):e7181
references.pmid: 19787069
references.citation: EMBO J. 1989 Oct;8(10):2975-81
references.pmid: 2583089
references.citation: PLoS One. 2010 Nov 05;5(11):e13828
references.pmid: 21079779
references.citation: PLoS One. 2009 Oct 21;4(10):e7535
references.pmid: 19844573
references.citation: J Biol Chem. 2002 Jan 25;277(4):2657-65
references.pmid: 11714693
references.citation: Breast Cancer Res. 2000;2(3):184-90
references.pmid: 11250708
references.citation: Cell Res. 2005 Jul;15(7):483-94
references.pmid: 16045811
references.citation: Breast Cancer Res. 2007;9(4):R47
references.pmid: 17662123
references.citation: J Biol Chem. 2000 Jul 14;275(28):21255-61
references.pmid: 10801813
references.citation: Curr Med Chem. 2006;13(29):3483-92
references.pmid: 17168718
references.citation: FEBS J. 2010 Oct;277(19):3904-23
references.pmid: 20840587
references.citation: J Biol Chem. 2001 Apr 27;276(17):14178-86
references.pmid: 11297534
references.citation: PLoS One. 2010 May 24;5(5):e10767
references.pmid: 20532243
references.citation: Bone. 2004 Jan;34(1):65-79
references.pmid: 14751564
references.citation: Clin Cancer Res. 1999 May;5(5):1041-56
references.pmid: 10353737
references.citation: Cancer Cell. 2004 Jun;5(6):525-31
references.pmid: 15193255
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Semin Oncol. 2003 Jun;30(3 Suppl 7):3-14
references.pmid: 12840796
references.citation: Cancer. 1977 Jun;39(6 Suppl):2875-82
references.pmid: 141322
references.citation: Biochimie. 1999 Jul;81(7):733-44
references.pmid: 10492020
references.citation: J Biol Chem. 1998 Aug 14;273(33):21342-51
references.pmid: 9694895
references.citation: Carcinogenesis. 2002 Nov;23(11):1831-8
references.pmid: 12419831
references.citation: Oncogene. 2000 Dec 27;19(56):6550-65
references.pmid: 11426640
references.citation: Prog Clin Biol Res. 1990;354A:179-91
references.pmid: 2247487
references.citation: Breast Cancer Res Treat. 1997 May;43(3):247-58
references.pmid: 9150904
references.citation: J Cancer Res Clin Oncol. 1999 Aug-Sep;125(8-9):520-4
references.pmid: 10480346
references.citation: PLoS One. 2009 Jun 16;4(6):e5933
references.pmid: 19529774
references.citation: J Am Soc Nephrol. 2001 Dec;12(12):2609-2615
references.pmid: 11729229
references.citation: Clin Cancer Res. 1998 Apr;4(4):963-71
references.pmid: 9563891
references.citation: Oncogene. 2007 May 14;26(22):3291-310
references.pmid: 17496923
references.citation: Biochem Biophys Res Commun. 1985 Apr 30;128(2):898-905
references.pmid: 2986629
references.citation: J Natl Cancer Inst. 1982 Aug;69(2):371-80
references.pmid: 6287076
references.citation: PLoS One. 2010 Jul 14;5(7):e11584
references.pmid: 20644732
references.citation: Matrix Biol. 2005 Feb;24(1):3-13
references.pmid: 15748997
references.citation: PLoS One. 2010 Apr 19;5(4):e10226
references.pmid: 20419107
references.citation: FASEB J. 2004 Apr;18(6):754-6
references.pmid: 14766798
references.citation: FASEB J. 2004 Apr;18(6):779-81
references.pmid: 14977887
references.citation: Mol Biol Cell. 2006 Apr;17(4):2009-20
references.pmid: 16452631
references.citation: Biochem J. 2001 Oct 1;359(Pt 1):1-16
references.pmid: 11563964
references.citation: Mol Biol Cell. 2001 Apr;12(4):863-79
references.pmid: 11294892
references.citation: Cell Mol Life Sci. 2000 Feb;57(2):276-89
references.pmid: 10766023
references.citation: Cancer Treat Rev. 1999 Oct;25(5):271-7
references.pmid: 10544071
references.citation: J Cell Sci. 2004 Nov 15;117(Pt 24):5887-95
references.pmid: 15522894
references.citation: Oncologist. 2003;8(1):5-17
references.pmid: 12604728
references.citation: Oncogene. 2000 Feb 21;19(8):1065-71
references.pmid: 10713691
references.citation: Br J Cancer. 2006 Jun 5;94(11):1604-9
references.pmid: 16685276
references.citation: PLoS One. 2009;4(2):e4527
references.pmid: 19223980
references.citation: Nat Cell Biol. 2009 Aug;11(8):1031-8
references.pmid: 19633662
references.citation: PLoS One. 2009 Jul 13;4(7):e6220
references.pmid: 19593441
references.citation: PLoS One. 2009 Dec 24;4(12):e8461
references.pmid: 20041153
references.citation: Int J Oncol. 2003 Feb;22(2):237-52
references.pmid: 12527919
references.citation: J Cell Sci. 2004 May 1;117(Pt 11):2227-37
references.pmid: 15126624
references.citation: PLoS One. 2008 Jun 18;3(6):e2420
references.pmid: 18560585
references.citation: Biochim Biophys Acta. 1998 Oct 1;1400(1-3):195-211
references.pmid: 9748575
references.citation: Histochem J. 1997 Jan;29(1):21-30
references.pmid: 9088942
references.citation: Biochem J. 2001 Feb 15;354(Pt 1):199-207
references.pmid: 11171095
references.citation: Steroids. 1975 Dec;26(6):785-95
references.pmid: 175527
references.citation: PLoS One. 2008 Aug 06;3(8):e2881
references.pmid: 18682844
references.citation: Cancer Res. 1992 Mar 15;52(6):1399-405
references.pmid: 1540948
references.citation: Clin Cancer Res. 2002 Apr;8(4):1054-60
references.pmid: 11948113
references.citation: Drugs. 2005;65(17):2513-31
references.pmid: 16296875
references.citation: Clin Pharmacokinet. 1999 Feb;36(2):99-114
references.pmid: 10092957
references.citation: PLoS One. 2009;4(4):e5342
references.pmid: 19399184
references.citation: J Biol Chem. 2002 Apr 5;277(14):12294-301
references.pmid: 11805102