title: MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression.
abstract: Paclitaxel (Taxol) is an effective chemotherapeutic agent for treatment of cancer patients. Despite impressive initial clinical responses, the majority of patients eventually develop some degree of resistance to Taxol-based therapy. The mechanisms underlying cancer cells resistance to Taxol are not fully understood. MicroRNA (miRNA) has emerged to play important roles in tumorigenesis and drug resistance. However, the interaction between the development of Taxol resistance and miRNA has not been previously explored. In this study we utilized a miRNA array to compare the differentially expressed miRNAs in Taxol-resistant and their Taxol-sensitive parental cells. We verified that miR-125b, miR-221, miR-222, and miR-923 were up-regulated in Taxol-resistant cancer cells by real-time PCR. We further investigated the role and mechanisms of miR-125b in Taxol resistance. We found that miR-125b was up-regulated in Taxol-resistant cells, causing a marked inhibition of Taxol-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to Taxol in cancer cells. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) is a direct target of miR-125b. Down-regulation of Bak1 suppressed Taxol-induced apoptosis and led to an increased resistance to Taxol. Restoring Bak1 expression by either miR-125b inhibitor or re-expression of Bak1 in miR-125b-overexpressing cells recovered Taxol sensitivity, overcoming miR-125-mediated Taxol resistance. Taken together, our data strongly support a central role for miR-125b in conferring Taxol resistance through the suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming Taxol resistance in a number of different tumor histologies.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Xi
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Adam I
authors.initials: AI
authors.lastname: Riker
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D017239:Paclitaxel
references.citation: Biochem Biophys Res Commun. 2008 Dec 5;377(1):114-9
references.pmid: 18834855
references.citation: Adv Exp Med Biol. 2007;608:119-29
references.pmid: 17993237
references.citation: Clin Exp Metastasis. 1997 May;15(3):272-306
references.pmid: 9174129
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19983-8
references.pmid: 18056640
references.citation: Int J Cancer. 2009 May 1;124(9):2236-42
references.pmid: 19127597
references.citation: Cancer Res. 2004 May 15;64(10):3479-85
references.pmid: 15150101
references.citation: Cancer Res. 2005 Aug 15;65(16):7065-70
references.pmid: 16103053
references.citation: EMBO J. 2007 Aug 8;26(15):3699-708
references.pmid: 17627278
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9779-84
references.pmid: 12902540
references.citation: Gastroenterology. 2009 May;136(5):1689-700
references.pmid: 19422085
references.citation: J Biol Chem. 2007 Jan 12;282(2):1479-86
references.pmid: 17110380
references.citation: Nucleic Acids Res. 2010 Jun;38(10):3222-32
references.pmid: 20144951
references.citation: Cell Physiol Biochem. 2009;23(4-6):347-58
references.pmid: 19471102
references.citation: Int J Cancer. 2009 Jul 15;125(2):345-52
references.pmid: 19378336
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1949-54
references.pmid: 18238902
references.citation: Nat Struct Mol Biol. 2009 Jan;16(1):23-9
references.pmid: 19079265
references.citation: Nature. 2000 Feb 24;403(6772):901-6
references.pmid: 10706289
references.citation: Mol Cell. 2002 May;9(5):993-1004
references.pmid: 12049736
references.citation: Clin Cancer Res. 2008 May 1;14(9):2690-5
references.pmid: 18451233
references.citation: Annu Rev Biochem. 1993;62:385-427
references.pmid: 8102521
references.citation: Genes Dev. 2009 Apr 1;23(7):862-76
references.pmid: 19293287
references.citation: Cancer Res. 2009 Feb 15;69(4):1279-83
references.pmid: 19190326
references.citation: Cancer Res. 2007 Sep 15;67(18):8699-707
references.pmid: 17875710
references.citation: Cell. 1994 Aug 26;78(4):539-42
references.pmid: 8069905
references.citation: J Biol Chem. 2008 Nov 7;283(45):31079-86
references.pmid: 18790736
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1326-34
references.pmid: 19228734
references.citation: J Biol Chem. 2007 Aug 10;282(32):23716-24
references.pmid: 17569667
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11358-62
references.pmid: 7972064
references.citation: Oncogene. 2008 Mar 13;27(12):1788-93
references.pmid: 17891175
references.citation: Cell. 2009 Aug 7;138(3):592-603
references.pmid: 19665978
references.citation: Gynecol Oncol. 1995 Feb;56(2):231-4
references.pmid: 7534740
references.citation: Dev Biol. 1999 Dec 15;216(2):671-80
references.pmid: 10642801
references.citation: Genes Dev. 2003 Dec 1;17(23):2922-32
references.pmid: 14633975
references.citation: Cancer Res. 2009 Jul 1;69(13):5292-3
references.pmid: 19549886
references.citation: Genes Chromosomes Cancer. 2009 Jul;48(7):569-82
references.pmid: 19396866
references.citation: PLoS Pathog. 2009 Dec;5(12):e1000681
references.pmid: 19997496
references.citation: Oncogene. 2009 Oct 22;28(42):3689-701
references.pmid: 19668225
references.citation: Cell Death Differ. 2002 Jun;9(6):636-42
references.pmid: 12032672
references.citation: Cancer Res. 2003 Mar 15;63(6):1207-13
references.pmid: 12649178
references.citation: J Biol Chem. 1999 Aug 13;274(33):22932-40
references.pmid: 10438458
references.citation: Mol Cancer. 2010 Feb 09;9:33
references.pmid: 20144215
references.citation: Oncogene. 2007 Nov 29;26(54):7590-5
references.pmid: 17563749
references.citation: Nat Cell Biol. 2008 Feb;10(2):202-10
references.pmid: 18193036
references.citation: JAMA. 2007 May 2;297(17):1901-8
references.pmid: 17473300
references.citation: Nat Med. 2008 Nov;14(11):1271-7
references.pmid: 18931683
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11737-42
references.pmid: 11562465
references.citation: Oncogene. 2009 Jan 8;28(1):140-5
references.pmid: 18836483
references.citation: Gynecol Oncol. 2008 Dec;111(3):478-86
references.pmid: 18823650
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5166-71
references.pmid: 18362358
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: EMBO Rep. 2009 Apr;10(4):400-5
references.pmid: 19247375
references.citation: J Exp Med. 2008 Oct 27;205(11):2499-506
references.pmid: 18936236
references.citation: Nucleic Acids Res. 2006 Jan 23;34(2):e13
references.pmid: 16432257
references.citation: Nat Rev Cancer. 2006 Nov;6(11):857-66
references.pmid: 17060945
references.citation: Int J Cancer. 2009 Sep 15;125(6):1328-33
references.pmid: 19437538
references.citation: Cancer Chemother Pharmacol. 2007 Feb;59(2):235-49
references.pmid: 16972069