IL6 sensitizes prostate cancer to the antiproliferative effect of IFNα2 through IRF9

Holger H H Erb,Frédéric R Santer,Bettina Schlick,Patrizia L Moser,Zoran Culig,Regina V Langlechner,Brett Hall,Kate Sasser,Karin Verstraeten,Florian Handle,Georg Schäfer,Tineke Casneuf

doi:10.1530/erc-13-0222

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.

Highlights

According to the Global Cancer Statistics of 2011, prostate cancer (PCa) has the second highest incidence worldwide with 903 500 new cases in 2008 and 258 400 deaths (Jemal et al 2011)
It was found that interleukin 6 (IL6) induces transcription of IRF9 by C/EBP-b binding to the g-IFN-activated transcriptional element
Stimulation with type I IFN leads to the formation of the transcriptionally active complex IFN-stimulated gene factor 3 (ISGF3) consisting of IRF9, STAT1, and STAT2 (Darnell et al 1994)

Summary

Introduction

According to the Global Cancer Statistics of 2011, prostate cancer (PCa) has the second highest incidence worldwide with 903 500 new cases in 2008 and 258 400 deaths (Jemal et al 2011). PCa is treated successfully either by surgery or by radiation therapy. In advanced stages of PCa, withdrawal of androgens is a standard therapy aimed at disease regression. In most cases, this therapy effect is transient, and the tumor relapses into a form of an aggressive castrationresistant PCa (CRPCa; Grossmann et al 2001). These therapies prolong survival only for about 2–3 months (Armstrong et al 2010, Rane et al 2012)

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