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Review
. 2012 Sep 5;360(1-2):52-8.
doi: 10.1016/j.mce.2011.05.033. Epub 2011 Jun 1.

Interleukin-6: a multifunctional targetable cytokine in human prostate cancer

Zoran Culig  1 , Martin Puhr
Affiliations
Review

Interleukin-6: a multifunctional targetable cytokine in human prostate cancer

Zoran Culig et al. Mol Cell Endocrinol. .

Abstract

Several cytokines are involved in regulation of cellular events in prostate cancer. Interleukin-6 (IL-6) was frequently investigated in prostate cancer models because of its increased expression in cancer tissue at early stages of the disease. In patients with metastatic prostate cancer, it is well-known that IL-6 levels increase in serum. High levels of IL-6 were measured in the supernatants of cells which do not respond to androgenic stimulation. IL-6 expression in prostate cancer increases due to enhanced expression of transforming growth factor-beta, and members of the activating protein-1 complex, and loss of the retinoblastoma tumour suppressor. IL-6 activation of androgen receptor (AR) may contribute to progression of a subgroup of prostate cancers. Results obtained with two prostate cancer cell lines, LNCaP and MDA PCa 2b, indicate that IL-6 activation of AR may cause either stimulatory or inhibitory responses on proliferation. Interestingly, prolonged treatment with IL-6 led to establishment of an IL-6 autocrine loop, suppressed signal transducer and activator of transcription (STAT)3 activation, and increased mitogen-activated protein kinase phosphorylation. In several cell lines IL-6 acts as a survival molecule through activation of the signalling pathway of phosphotidylinositol 3-kinase. Expression of suppressors of cytokine signalling (SOCS) has been studied in prostate cancer. SOCS-3 prevents phosphorylation of STAT3 and is an important anti-apoptotic factor in AR-negative prostate cancer cells. Experimental therapy against IL-6 in prostate cancer is based on the use of the monoclonal antibody siltuximab which may be used for personalised therapy coming in the future.

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Figures

Fig. 1
Fig. 1
The mechanisms by which SOCS proteins inhibit IL-6-mediated signal transduction. SOCS may prevent IL-6 signalling through binding to the receptor, inhibiting JAK, or enhancing ubiquitination (LB = ligand binding, ST = signal transduction).
Fig. 2
Fig. 2
Anti-IL-6 antibody siltuximab was used in prostate cancer cell lines, studies with xenografts, and in a clinical phase II study.
See this image and copyright information in PMC

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