title: Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition.
abstract: Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF‑κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N‑cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR‑200, miR‑303, miR‑302, miR‑199 and miR‑328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.
authors: Department of Medicine, Section of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors: James W
authors: JW
authors: Antoon
authors: Ashley M
authors: AM
authors: Nitzchke
authors: Elizabeth C
authors: EC
authors: Martin
authors: Lyndsay V
authors: LV
authors: Rhodes
authors: Seungyoon
authors: S
authors: Nam
authors: Scott
authors: S
authors: Wadsworth
authors: Virgilo A
authors: VA
authors: Salvo
authors: Steven
authors: S
authors: Elliott
authors: Bridgette
authors: B
authors: Collins-Burow
authors: Kenneth P
authors: KP
authors: Nephew
authors: Matthew E
authors: ME
authors: Burow
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D035683:MicroRNAs; D011725:Pyridines; C400277:RWJ 67657; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases
references: J Clin Invest. 2004 Aug;114(4):569-81
references: 15314694
references: Med Oncol. 2010 Jun;27(2):406-15
references: 19412672
references: Endocrinology. 2012 Feb;153(2):925-36
references: 22166980
references: J Biol Chem. 2001 Jun 1;276(22):18934-40
references: 11259436
references: Cancer Chemother Pharmacol. 2010 May;65(6):1191-5
references: 20155475
references: J Endocrinol. 2012 Jul;214(1):45-54
references: 22562654
references: J Biol Chem. 2010 Nov 19;285(47):36721-35
references: 20843787
references: Breast Cancer Res Treat. 1993;24(3):227-39
references: 8435478
references: J Biol Chem. 2001 Dec 14;276(50):46792-7
references: 11579095
references: Nature. 2007 Oct 11;449(7163):682-8
references: 17898713
references: Cell Signal. 2008 Jul;20(7):1368-74
references: 18450422
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17408-13
references: 21969554
references: EMBO J. 2007 Aug 8;26(15):3699-708
references: 17627278
references: Methods Mol Med. 2005;111:127-48
references: 15911977
references: Cancer Res. 2008 Jan 15;68(2):425-33
references: 18199536
references: Histochem Cell Biol. 2000 Mar;113(3):189-94
references: 10817673
references: Mol Endocrinol. 2006 May;20(5):971-83
references: 16410316
references: Oncol Rep. 2012 Jun;27(6):1779-86
references: 22469881
references: Breast Cancer Res Treat. 2010 Jun;121(2):293-300
references: 19597705
references: Surgery. 2002 Aug;132(2):293-301
references: 12219026
references: Cancer Res. 2006 Apr 1;66(7):3365-9
references: 16585154
references: Anal Biochem. 2000 Oct 15;285(2):194-204
references: 11017702
references: Surgery. 2001 Aug;130(2):143-50
references: 11490342
references: Cancer Res. 2008 Feb 1;68(3):826-33
references: 18245484
references: Carcinogenesis. 2004 Feb;25(2):249-61
references: 14604893
references: J Cell Physiol. 2011 May;226(5):1248-54
references: 20945383
references: J Cell Biochem. 2001;82(4):556-65
references: 11500933
references: Oncogenesis. 2012 Mar 12;1:e3
references: 23552555
references: Cancer Res. 1994 Feb 1;54(3):825-31
references: 7905787
references: Exp Cell Res. 2000 Apr 10;256(1):42-9
references: 10739650
references: J Biol Chem. 2001 Apr 6;276(14):10759-66
references: 11148204
references: Sci Rep. 2012;2:539
references: 22844580
references: J Natl Cancer Inst. 2010 May 19;102(10):706-21
references: 20388878
references: Physiol Rev. 2001 Apr;81(2):807-69
references: 11274345
references: Cell Res. 2008 Mar;18(3):350-9
references: 18270520
references: J Med Chem. 2009 Sep 24;52(18):5748-52
references: 19694470
references: Bioorg Med Chem Lett. 2012 Apr 1;22(7):2624-8
references: 22366655
references: Nat Cell Biol. 2007 Apr;9(4):361-3
references: 17401385
references: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5375-80
references: 20212154
references: J Steroid Biochem Mol Biol. 2012 Oct;132(1-2):186-93
references: 22634477
references: J Steroid Biochem Mol Biol. 2002 Feb;80(2):239-56
references: 11897507
references: Am J Cancer Res. 2012;2(4):446-58
references: 22860234
references: Oncogene. 2007 Apr 26;26(19):2799-803
references: 17072344
references: Semin Oncol. 1996 Feb;23(1 Suppl 2):55-9
references: 8614846
references: J Mol Endocrinol. 2008 Apr;40(4):173-84
references: 18372406
references: J Biol Chem. 2002 Nov 22;277(47):45695-703
references: 12244117
references: Biochem Biophys Res Commun. 2000 May 10;271(2):342-5
references: 10799299
references: J Mol Endocrinol. 2011 Apr 28;46(3):205-16
references: 21321095
references: Endocrinology. 2010 Nov;151(11):5124-35
references: 20861237
references: J Steroid Biochem Mol Biol. 2005 Feb;94(1-3):23-37
references: 15862947
references: EMBO Rep. 2008 Jun;9(6):582-9
references: 18483486
references: J Cell Sci. 2010 Dec 15;123(Pt 24):4321-31
references: 21098640
references: Genes Dev. 2008 Apr 1;22(7):894-907
references: 18381893
references: Int J Cancer. 1992 Dec 2;52(6):953-8
references: 1459736
references: Bioinformatics. 2009 Feb 15;25(4):430-4
references: 19091772
references: Breast Cancer Res. 2008;10(6):R105
references: 19087274
references: Cancer Gene Ther. 2010 Aug;17(8):523-31
references: 20467450
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17349-54
references: 21969564
references: Int J Oncol. 2012 May;40(5):1553-60
references: 22293682
references: J Biol Chem. 2000 Sep 8;275(36):27694-702
references: 10874044
references: PLoS One. 2012;7(2):e31060
references: 22347428
references: Cancer Res. 2011 Jan 15;71(2):603-13
references: 21123450
references: Cell Growth Differ. 2001 Aug;12(8):397-408
references: 11504705
references: Cell Cycle. 2006 Apr;5(8):824-8
references: 16627995
references: Oncol Rep. 2012 Jan;27(1):10-6
references: 21971930
references: J Pharmacol Exp Ther. 1999 Nov;291(2):680-7
references: 10525088
references: J Biol Chem. 2001 Feb 23;276(8):5676-84
references: 11069918
references: Genome Med. 2011 Nov 28;3(11):77
references: 22122801
references: Cancer Invest. 2012 Feb;30(2):135-48
references: 22250588
references: Mol Carcinog. 2009 Sep;48(9):862-71
references: 19263441
references: Int J Oncol. 2004 Jun;24(6):1473-80
references: 15138590
references: Exp Biol Med (Maywood). 2012 Jul;237(7):832-44
references: 22859737
references: Clin Cancer Res. 2007 Apr 1;13(7):1950-4
references: 17404074
references: Nat Rev Genet. 2009 Oct;10(10):704-14
references: 19763153
references: Toxicol Lett. 2005 Feb 15;155(2):227-38
references: 15603917
references: Cancer Res. 1995 Jan 15;55(2):399-407
references: 7529136
references: Oncology. 1999 Oct;57 Suppl 2:37-44
references: 10545801
references: Annu Rev Med. 2002;53:615-27
references: 11818492
references: Arthritis Rheum. 2010 May;62(5):1361-71
references: 20131257
references: Cancer Biol Ther. 2012 Sep;13(11):1026-33
references: 22825349
references: Cancer Lett. 2010 Dec 18;299(1):29-36
references: 20732742
references: Mol Pharmacol. 2008 May;73(5):1394-404
references: 18252806
references: J Pharmacol Exp Ther. 2004 May;309(2):523-32
references: 14742741
references: Cell. 1995 May 19;81(4):495-504
references: 7758105
references: EMBO J. 1999 Dec 1;18(23):6845-54
references: 10581258
references: Mol Cancer Ther. 2008 Jul;7(7):2152-9
references: 18645025
references: Mol Cancer. 2010 Nov 18;9:295
references: 21087507
references: Hepatology. 2010 May;51(5):1614-23
references: 20209605
references: Mol Endocrinol. 1989 Apr;3(4):687-93
references: 2725532
references: Cancer Biol Ther. 2011 Apr 1;11(7):678-89
references: 21307639