title: IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9.
abstract: Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNα2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2.
authors.affiliation: Division of Experimental Urology, Department of Urology, Innsbruck Medical University, Austria.
authors.forename: Holger H H
authors.initials: HH
authors.lastname: Erb
authors.forename: Regina V
authors.initials: RV
authors.lastname: Langlechner
authors.forename: Patrizia L
authors.initials: PL
authors.lastname: Moser
authors.forename: Florian
authors.initials: F
authors.lastname: Handle
authors.forename: Tineke
authors.initials: T
authors.lastname: Casneuf
authors.forename: Karin
authors.initials: K
authors.lastname: Verstraeten
authors.forename: Bettina
authors.initials: B
authors.lastname: Schlick
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.forename: Brett
authors.initials: B
authors.lastname: Hall
authors.forename: Kate
authors.initials: K
authors.lastname: Sasser
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.forename: Frédéric R
authors.initials: FR
authors.lastname: Santer
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C494227:IRF9 protein, human; C504234:siltuximab
keywords: IFNα2; IL6; IRF9; inflammation; prostate cancer
references.citation: Cancer Res. 2002 Oct 15;62(20):5720-6
references.pmid: 12384530
references.citation: Cancer Res. 1997 Jan 1;57(1):141-6
references.pmid: 8988055
references.citation: Nat Rev Immunol. 2006 Aug;6(8):602-12
references.pmid: 16868551
references.citation: Cancer. 1984 Dec 1;54(11 Suppl):2770-6
references.pmid: 6208992
references.citation: Prostate. 2012 Dec 1;72(16):1719-35
references.pmid: 22473339
references.citation: J Natl Cancer Inst. 2001 Nov 21;93(22):1687-97
references.pmid: 11717329
references.citation: Mol Cancer Ther. 2009 Mar;8(3):665-71
references.pmid: 19240160
references.citation: Cancer Res. 2001 Dec 15;61(24):8851-8
references.pmid: 11751408
references.citation: J Pathol. 2000 Jul;191(3):239-44
references.pmid: 10878544
references.citation: Mol Med. 1999 Jul;5(7):432-56
references.pmid: 10449805
references.citation: J Cell Biochem. 2005 Jun 1;95(3):497-505
references.pmid: 15838876
references.citation: Oncogene. 2007 May 3;26(20):2822-32
references.pmid: 17072336
references.citation: Adv Exp Med Biol. 2008;617:547-55
references.pmid: 18497081
references.citation: Oncogene. 2006 Oct 5;25(45):6113-22
references.pmid: 16652143
references.citation: Nat Rev Urol. 2012 Oct;9(10):595-602
references.pmid: 22890299
references.citation: Curr Opin Investig Drugs. 2005 Jun;6(6):639-45
references.pmid: 15988916
references.citation: Urol Res. 1989;17(2):111-5
references.pmid: 2734978
references.citation: Clin Cancer Res. 2003 Oct 15;9(13):4653-65
references.pmid: 14581334
references.citation: Eur J Cancer. 2010 Jan;46(2):284-97
references.pmid: 19906524
references.citation: Cancer Res. 2001 Sep 1;61(17):6540-7
references.pmid: 11522652
references.citation: Am J Pathol. 2001 Dec;159(6):2159-65
references.pmid: 11733366
references.citation: Am J Pathol. 2012 May;180(5):2097-107
references.pmid: 22449952
references.citation: Nucleic Acids Res. 2005 Nov 10;33(20):e175
references.pmid: 16284200
references.citation: Nucleic Acids Res. 2003 Feb 15;31(4):e15
references.pmid: 12582260
references.citation: J Interferon Res. 1986 Dec;6(6):713-5
references.pmid: 3572090
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: J Urol. 1994 May;151(5):1396-9
references.pmid: 7512667
references.citation: Tex Rep Biol Med. 1981-1982;41:626-33
references.pmid: 6763369
references.citation: Prostate. 1999 Oct 1;41(2):127-33
references.pmid: 10477909
references.citation: Clin Cancer Res. 2001 Sep;7(9):2941-8
references.pmid: 11555613
references.citation: Biochim Biophys Acta. 2011 Feb;1813(2):308-14
references.pmid: 21167870
references.citation: Clin Cancer Res. 2000 Jul;6(7):2702-6
references.pmid: 10914713
references.citation: Cancer Treat Res. 2003;115:267-91
references.pmid: 12613201
references.citation: J Cell Physiol. 2005 Feb;202(2):323-35
references.pmid: 15389589
references.citation: J Urol. 1999 Jan;161(1):182-7
references.pmid: 10037394
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):203-11
references.pmid: 20008841
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14565-70
references.pmid: 11734652
references.citation: J Immunother. 2009 Oct;32(8):803-16
references.pmid: 19752753
references.citation: Cancer Res. 1990 Dec 15;50(24):7786-8
references.pmid: 2253221
references.citation: Oncogene. 1997 Mar 13;14(10):1165-70
references.pmid: 9121765
references.citation: Adv Immunol. 1993;54:1-78
references.pmid: 8379461
references.citation: Prostate. 2011 Sep 15;71(13):1455-65
references.pmid: 21321981
references.citation: J Interferon Cytokine Res. 1999 Dec;19(12):1351-61
references.pmid: 10638704
references.citation: Methods Mol Biol. 2003;224:111-36
references.pmid: 12710670
references.citation: Biochim Biophys Acta. 2000 Jun 21;1492(1):163-71
references.pmid: 11004486
references.citation: Semin Oncol. 2002 Jun;29(3 Suppl 7):18-26
references.pmid: 12068384
references.citation: Expert Opin Biol Ther. 2012 Aug;12(8):1087-99
references.pmid: 22694288
references.citation: Cancer Sci. 2011 Aug;102(8):1576-81
references.pmid: 21535317
references.citation: Bioinformatics. 2007 Nov 1;23(21):2897-902
references.pmid: 17921172