title: Silencing dishevelled-1 sensitizes paclitaxel-resistant human ovarian cancer cells via AKT/GSK-3β/β-catenin signalling.
abstract: OBJECTIVE
  Expression of dishevelled-1 (DVL1) has recently been linked to cancer progression, however, its role in resistance to cancer therapy is unclear. In this study, we aimed to explore the function of DVL1 in paclitaxel-resistant human ovarian cancer cells.
  
  
  METHODS
  The MTT assay was used to assess effects of DVL1 silencing on sensitivity of cells that were otherwise resistant to paclitaxel (Taxol). Western blotting and immunofluorescence staining were used to examine effects of DVL1 on AKT/GSK-3β/β-catenin signalling.
  
  
  RESULTS
  Dishevelled-1 was found to be over-expressed in a paclitaxel-resistant cell line derived from human ovarian cancer cell line A2780 (A2780/Taxol line) as well as parental A2780 cells. Down-regulation of DVL1 (using the inhibitor 3289-8625 or siRNA (siDVL1) against DVL1) sensitized A2780/Taxol cells to paclitaxel. Over-expression of DVL1 in A2780 cells increased protein levels of P-gp, BCRP and Bcl-2, which are known targets of β-catenin. Silencing DVL1 in A2780/Taxol cells also reduced levels of these proteins, and led to accumulation of β-catenin. In addition, DVL1 aberrantly activated AKT/GSK-3β/β-catenin signalling. Inactivation of AKT signalling attenuated DVL1-mediated inhibition of GSK-3β and accumulation of β-catenin, in both A2780 and A2780/Taxol cells.
  
  
  CONCLUSIONS
  Taken together, these results suggest that silencing DVL1 sensitized A2780/Taxol cells to paclitaxel, by down-regulating AKT/GSK-3β/β-catenin signalling, providing a novel strategy for chemosensitization of ovarian cancer to paclitaxel-induced cytotoxicity.
authors: School of Biomedicine Sciences, Chengdu Medical College, Chengdu, 610500, China.
authors: Kun
authors: K
authors: Zhang
authors: Haixing
authors: H
authors: Song
authors: Ping
authors: P
authors: Yang
authors: Xiaozhen
authors: X
authors: Dai
authors: Ya
authors: Y
authors: Li
authors: Lan
authors: L
authors: Wang
authors: Jun
authors: J
authors: Du
authors: Kejian
authors: K
authors: Pan
authors: Tao
authors: T
authors: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000072261:Dishevelled Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D017239:Paclitaxel
references: Gynecol Oncol. 2014 Jul;134(1):112-20
references: 24736023
references: J Cell Sci. 2010 May 1;123(Pt 9):1588-99
references: 20388731
references: Phytother Res. 2009 Jul;23(7):933-7
references: 19172664
references: Curr Drug Targets. 2006 Jul;7(7):893-909
references: 16842220
references: Protein Sci. 2009 May;18(5):994-1002
references: 19388021
references: Oncogene. 2009 Jun 11;28(23):2245-56
references: 19421142
references: Curr Cancer Drug Targets. 2012 Oct;12(8):987-97
references: 22515523
references: J Biol Chem. 1999 Jul 30;274(31):21790-6
references: 10419494
references: Oncogene. 2007 Sep 13;26(42):6194-202
references: 17404573
references: Hum Pathol. 2013 Nov;44(11):2373-84
references: 23850493
references: N Engl J Med. 2006 Jan 5;354(1):34-43
references: 16394300
references: Nat Rev Cancer. 2003 Jul;3(7):502-16
references: 12835670
references: Front Pharmacol. 2014 Jul 10;5:159
references: 25071577
references: Exp Oncol. 2013 Dec;35(4):287-90
references: 24382439
references: Ann Oncol. 2013 Dec;24 Suppl 10:x69-x76
references: 24265409
references: Anticancer Res. 2010 Jun;30(6):2041-8
references: 20651349
references: Int J Neuropsychopharmacol. 2012 Aug;15(7):965-79
references: 21777508
references: Klin Onkol. 2012;25(6):457-63
references: 23301649
references: Cancer Res. 2013 Dec 1;73(23):6998-7008
references: 24097825
references: Dev Cell. 2009 Jul;17(1):9-26
references: 19619488
references: Pigment Cell Melanoma Res. 2014 Sep;27(5):764-76
references: 24902993
references: Cancer Sci. 2013 Oct;104(10):1303-8
references: 23822562
references: Clin Cancer Res. 2010 Jan 15;16(2):600-9
references: 20068074
references: Int J Mol Sci. 2014 Jul 17;15(7):12665-76
references: 25036031
references: Cancer Sci. 2003 Jun;94(6):515-8
references: 12824876
references: Gynecol Oncol. 2013 Dec;131(3):772-9
references: 24125749
references: J Neurochem. 2008 Aug;106(4):1855-65
references: 18624906
references: Ann N Y Acad Sci. 2007 Jan;1095:82-9
references: 17404021
references: Am J Cancer Res. 2014 May 26;4(3):285-92
references: 24959383
references: Mol Cancer Ther. 2008 Jun;7(6):1633-8
references: 18566234
references: Cancer Res. 2011 Dec 1;71(23):7280-90
references: 21990322
references: Mol Carcinog. 2014 Feb;53 Suppl 1:E169-80
references: 24151146
references: Oncogene. 2013 May 30;32(22):2767-81
references: 22797058
references: Int J Neuropsychopharmacol. 2014 Sep;17(9):1511-9
references: 24641999
references: Mol Carcinog. 2010 Aug;49(8):760-70
references: 20572159
references: Int J Toxicol. 2006 Jul-Aug;25(4):231-59
references: 16815813
references: Trends Pharmacol Sci. 2014 Feb;35(2):103-9
references: 24365576
references: Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E152-8
references: 16478782
references: J Gynecol Oncol. 2014 Jul;25(3):236-48
references: 25045437
references: Methods Mol Biol. 2009;472:413-37
references: 19107446
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: Cell Signal. 2010 May;22(5):717-27
references: 20006983
references: Cancer Cell. 2010 Dec 14;18(6):606-18
references: 21156284
references: Drug Metab Pharmacokinet. 2012;27(1):85-105
references: 22123128
references: J Cell Sci. 2007 Jul 15;120(Pt 14):2402-12
references: 17606995
references: Biochim Biophys Acta. 2008 Nov;1782(11):649-57
references: 18930135
references: Cancer Lett. 2011 Dec 8;311(2):230-6
references: 21880414
references: J Biol Chem. 2001 May 18;276(20):17479-83
references: 11278246
references: EMBO J. 1996 Sep 2;15(17):4526-36
references: 8887544
references: Nat Struct Mol Biol. 2007 Jun;14(6):484-92
references: 17529994
references: Ann N Y Acad Sci. 2011 Jul;1229:53-60
references: 21793839
references: Tumori. 2005 Nov-Dec;91(6):546-51
references: 16457155
references: Curr Med Chem. 2014;21(26):3009-20
references: 24735363
references: Int J Oncol. 2014 May;44(5):1736-44
references: 24585004
references: Mol Cell. 2003 Nov;12(5):1251-60
references: 14636582
references: Front Endocrinol (Lausanne). 2014 Feb 04;5:10
references: 24550888