Abstract
As an established mediator of inflammation, interleukin-6 (IL-6) is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. However, whether IL-6 has a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates the autocrine IL-6 loop and autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer the tumorigenic property and also that activation of signal transducer and activator of transcription 3 (STAT3) is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6-mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands, namely IGF-I and IGF-II. These findings indicate that IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer.
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Acknowledgements
This study was supported by the National Institute of Health (NIH) Temin Award 1K01CA116002, NIH 1R01CA149405 and DOD-USARMC IDEA Development Award W81XWH-06-1-0014 to JDW and partially supported by the Pacific Northwest Prostate Cancer SPORE P50-CA097186 (JDW) and the NIH Program Project Grant PO1 CA085859 (SRP) and P01 CA104177 (PBF). PBF holds the Thelma Newmeyer Corman Chair in Cancer Research at the VCU Massey Cancer Center.
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Rojas, A., Liu, G., Coleman, I. et al. IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene 30, 2345–2355 (2011). https://doi.org/10.1038/onc.2010.605
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DOI: https://doi.org/10.1038/onc.2010.605
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