IL‐18 is produced by prostate cancer cells and secreted in response to interferons

• Published in: International journal of cancer 2003-10, Vol.106 (6), p.827-835
• Main Authors: Lebel‐Binay, Sophie, Thiounn, Nicolas, De Pinieux, Gonzague, Vieillefond, Annick, Debré, Bernard, Bonnefoy, Jean‐Yves, Fridman, Wolf‐Herman, Pagès, Franck
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Biological and medical sciences; Caspase 1 - genetics; Caspase 1 - metabolism; Caspase Inhibitors; caspase‐1; Cell Division - drug effects; Cohort Studies; DNA Primers - chemistry; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; IFN‐α; IFN‐γ; IL‐18; Immunoenzyme Techniques; Interferon-alpha - pharmacology; Interferon-gamma - pharmacology; Interleukin-18 - biosynthesis; Interleukin-18 Receptor alpha Subunit; Male; Medical sciences; Nephrology. Urinary tract diseases; prognosis; prostate cancer; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Interleukin - metabolism; Receptors, Interleukin-18; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured - drug effects; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11285

Murine models have shown that IL‐18 has antiangiogenic and antitumor effects, but little is known about IL‐18 production in human tumors. We investigated IL‐18 expression in clinically localized prostate cancers by immunohistochemistry and showed that 75% of the prostate cancers studied (27/36 cases) presented with tumor cells producing IL‐18. Prostate tumor cell lines PC‐3, DU 145 and LNCaP synthesized the immature form of IL‐18 (p24). IFN‐γ produced in prostate cancers induced caspase‐1 mRNA and IL‐18 secretion of tumor cell lines, which was inhibited by the cell‐permeable Tyr‐Val‐Ala‐Asp‐aldehyde caspase‐1 inhibitor (YVAD‐CHO). Interestingly, IFN‐α also induced IL‐18 secretion of the poorly differentiated cell line PC‐3. PC‐3 and DU 145, but not the well‐differentiated cell line LNCaP, expressed IL‐18Rα (IL‐1Rrp) protein and transcripts for IL‐18Rβ (AcPL). Exogenous IL‐18 increased mitochondrial activity of both cell lines evaluated by the tetrazolium (MTT) assay but did not influence their proliferation. This indicated that prostate tumor cells could secrete IL‐18 in response to IFN‐γ in the tumor microenvironment and that IL‐18 could act as a autocrine/paracrine factor for the tumor. In the cohort of patients studied, IL‐18 expression in prostate cancers (with up to 10% of tumor cells stained) was associated with a favorable outcome and equally predictive as pathologic stage on multivariate analysis (log rank test, p = 0.02). Tumor IL‐18 production is a novel physiopathologic feature of prostate cancer and appears to be a favorable event in the course of the disease. Modulation of IL‐18 production by interferons could have a beneficial clinical effect, which deserves further investigation. © 2003 Wiley‐Liss, Inc.