title: A switch from canonical to noncanonical Wnt signaling mediates drug resistance in colon cancer cells.
abstract: Butyrate, a fermentation product of fiber in the colon, acts as a histone deacetylase inhibitor (HDACi) and induces apoptosis in colon cancer (CC) cells in vitro. We have reported that the apoptotic effects of butyrate are dependent upon the hyperactivation of the Wnt/beta-catenin pathway. However, prolonged exposure of CC cells to increasing concentrations of butyrate results in the acquisition of resistance to the Wnt/beta-catenin- and apoptosis-inducing effects of this agent, as well as cross-resistance to structurally different HDACis. Here we report that one mechanism whereby HDACi resistance arises is through the increase of beta-catenin-independent (noncanonical) Wnt signaling. Compared to HDACi-sensitive HCT-116 CC cells, HDACi-resistant HCT-R cells exhibit higher levels of AKT/PKB cell survival signaling, which is in part induced by WNT5A and its receptor ROR2. The induction of AKT signaling by HDACis is also detected in other CC cell lines, albeit to a lesser extent than in the drug-resistant HCT-R cells. The observations suggested that the apoptotic effect of butyrate and other HDACis in CC cells can be augmented by inhibitors of pAKT. In agreement with the hypothesis, the combination of MK2206, a pAKT inhibitor, and a HDACi (butyrate or LBH589) induced higher apoptosis in CC cells compared to each agent alone. The exposure to both agents also re-sensitized the HCT-R cells to apoptosis. Finally, the concept of simultaneously inducing canonical Wnt activity and suppressing AKT signaling was translated into a combination of diet-derived agents. Diet-derived pAKT inhibitors (caffeic acid phethyl ester, sulforaphane, dilallyl trisulfide) suppressed the butyrate-induced levels of pAKT, and increased the apoptotic effects of butyrate in both drug-sensitive and drug-resistant CC cells.Our findings can be translated into (a) CC therapy employing combinations of synthetic HDACis and inhibitors of pAKT, as well as (b) CC prevention based upon diets that result in sufficient amounts of butyrate and pAKT inhibitors.
authors.affiliation: Department of Basic Sciences, The Commonwealth Medical College, Scranton, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bordonaro
authors.forename: Shruti
authors.initials: S
authors.lastname: Tewari
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Cicco
authors.forename: Wafa
authors.initials: W
authors.lastname: Atamna
authors.forename: Darina L
authors.initials: DL
authors.lastname: Lazarova
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D051153:Wnt Proteins; D051057:Proto-Oncogene Proteins c-akt
references.citation: Biochim Biophys Acta. 1999 Oct 29;1424(2-3):M23-37
references.pmid: 10528152
references.citation: J Biol Chem. 2006 Jul 28;281(30):21040-21051
references.pmid: 16717102
references.citation: Cancer Res. 1999 Sep 15;59(18):4506-9
references.pmid: 10493496
references.citation: Int J Cancer. 2004 Jul 1;110(4):523-31
references.pmid: 15122584
references.citation: Int J Oncol. 2007 Apr;30(4):905-18
references.pmid: 17332930
references.citation: J Biol Chem. 2005 Dec 16;280(50):41342-51
references.pmid: 16251184
references.citation: N Engl J Med. 2000 Apr 20;342(16):1156-62
references.pmid: 10770980
references.citation: Biochem Biophys Res Commun. 2010 Oct 1;400(4):500-6
references.pmid: 20732301
references.citation: Mol Cell. 2009 Dec 11;36(5):885-93
references.pmid: 20005850
references.citation: Mol Pathol. 2002 Aug;55(4):220-6
references.pmid: 12147710
references.citation: J Biol Chem. 2002 Sep 20;277(38):34727-35
references.pmid: 12121999
references.citation: Mol Cell. 2009 Dec 11;36(5):894-9
references.pmid: 20005851
references.citation: J Thorac Cardiovasc Surg. 2005 Nov;130(5):1422-9
references.pmid: 16256798
references.citation: Cell. 1996 Oct 18;87(2):159-70
references.pmid: 8861899
references.citation: Mol Cancer Ther. 2010 Jul;9(7):1956-67
references.pmid: 20571069
references.citation: Nutr Cancer. 2008;60(3):412-20
references.pmid: 18444176
references.citation: Cell Signal. 2007 Dec;19(12):2498-506
references.pmid: 17804197
references.citation: Cancer Lett. 2011 Feb 28;301(2):168-76
references.pmid: 21168265
references.citation: Exp Cell Res. 2007 May 1;313(8):1652-66
references.pmid: 17359971
references.citation: Int J Mol Med. 2011 Jan;27(1):63-9
references.pmid: 21069266
references.citation: Dev Cell. 2008 Mar;14(3):399-410
references.pmid: 18331718
references.citation: Cell. 2000 Oct 13;103(2):311-20
references.pmid: 11057903
references.citation: Oncogene. 2010 Jan 7;29(1):34-44
references.pmid: 19802008
references.citation: Radiat Res. 2000 Mar;153(3):245-57
references.pmid: 10669545
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1193-8
references.pmid: 19144919
references.citation: Mol Cancer. 2004 Apr 26;3:11
references.pmid: 15109396
references.citation: Science. 1997 Mar 21;275(5307):1787-90
references.pmid: 9065402
references.citation: Cell Calcium. 2005 Sep-Oct;38(3-4):439-46
references.pmid: 16099039
references.citation: Nat Cell Biol. 2005 Jun;7(6):591-600
references.pmid: 15864305
references.citation: Carcinogenesis. 2006 Oct;27(10):2038-46
references.pmid: 16675473
references.citation: Cancer Res. 2007 Oct 15;67(20):9937-44
references.pmid: 17942926
references.citation: Cancer Res. 2009 Dec 15;69(24):9457-64
references.pmid: 19934323
references.citation: Clin Cancer Res. 2000 Mar;6(3):949-56
references.pmid: 10741720
references.citation: Science. 1997 Mar 14;275(5306):1652-4
references.pmid: 9054360
references.citation: J Biol Chem. 2009 Oct 30;284(44):30167-76
references.pmid: 19720827
references.citation: Mol Cancer Ther. 2009 Aug;8(8):2103-9
references.pmid: 19671746
references.citation: Trends Cell Biol. 2008 Nov;18(11):536-44
references.pmid: 18848778
references.citation: Mol Cancer Res. 2009 Aug;7(8):1189-96
references.pmid: 19671687
references.citation: Cancer Sci. 2009 Jul;100(7):1227-33
references.pmid: 19486338
references.citation: Mol Cell Biol. 1999 Aug;19(8):5743-58
references.pmid: 10409762
references.citation: Arthritis Rheum. 2010 Jan;62(1):159-70
references.pmid: 20039434
references.citation: PLoS Biol. 2006 Apr;4(4):e115
references.pmid: 16602827
references.citation: Carcinogenesis. 2004 Jan;25(1):83-90
references.pmid: 14514658
references.citation: Clin Exp Immunol. 2010 May;160(2):223-32
references.pmid: 20059479
references.citation: J Nutr Biochem. 2008 Sep;19(9):587-93
references.pmid: 18061431
references.citation: Nucleic Acids Res. 2010 Sep;38(17):5735-45
references.pmid: 20460455
references.citation: Oncol Res. 1995;7(9):445-52
references.pmid: 8835288
references.citation: Int J Clin Exp Pathol. 2010 Oct 12;3(8):768-74
references.pmid: 21151390
references.citation: Carcinogenesis. 2006 Mar;27(3):533-40
references.pmid: 16169930
references.citation: Cancer Res. 2000 Nov 1;60(21):6201-7
references.pmid: 11085546
references.citation: Curr Biol. 2004 Jul 27;14(14):1262-6
references.pmid: 15268856
references.citation: Dev Cell. 2004 Oct;7(4):491-501
references.pmid: 15469838
references.citation: J Biol Chem. 2008 Oct 10;283(41):27973-27981
references.pmid: 18667433
references.citation: Dev Dyn. 2010 Jan;239(1):1-15
references.pmid: 19530173
references.citation: Int J Biochem Cell Biol. 2010 Nov;42(11):1847-55
references.pmid: 20692358
references.citation: Bull Cancer. 2010 Feb;97(2):E9-E15
references.pmid: 20085858
references.citation: Development. 2004 Nov;131(22):5591-8
references.pmid: 15496444
references.citation: Mol Cell. 2009 Dec 11;36(5):872-84
references.pmid: 20005849
references.citation: Carcinogenesis. 2000 May;21(5):921-7
references.pmid: 10783313
references.citation: Br J Cancer. 1999 Oct;81(3):496-502
references.pmid: 10507776
references.citation: Dev Cell. 2003 Sep;5(3):367-77
references.pmid: 12967557
references.citation: Am J Respir Cell Mol Biol. 2009 Nov;41(5):583-9
references.pmid: 19251946
references.citation: Cell Growth Differ. 2001 Jun;12(6):319-26
references.pmid: 11432806
references.citation: J Agric Food Chem. 2007 May 2;55(9):3398-407
references.pmid: 17394337
references.citation: Curr Oncol Rep. 2010 Sep;12(5):314-8
references.pmid: 20603725
references.citation: Front Biosci. 2002 Feb 01;7:d376-89
references.pmid: 11815285
references.citation: J Cell Biol. 2003 Sep 1;162(5):899-908
references.pmid: 12952940
references.citation: Mol Cell Biol. 2008 Apr;28(8):2732-44
references.pmid: 18268006