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The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

Oncogene volume 26, pages 2822–2832 (2007)Cite this article

Abstract

Levels of the proinflammatory cytokine interleukin-6 (IL-6) are increased in therapy-resistant prostate cancer. IL-6 has been considered a positive growth factor in late-stage prostate cancer cells and a potential target for therapeutic interference. Effects of inhibition of IL-6 on cell survival were studied in LNCaP-IL6+ cells, a model system for advanced prostate cancer, which produce IL-6. We show that the autocrine IL-6 loop is responsible for resistance to apoptosis and increased cellular levels of myeloid cell leukemia-1 (Mcl-1) protein, an antiapoptotic member of the Bcl-2 family. Treatment of cells with a chimeric anti-IL-6 antibody (CNTO 328) led to the induction of apoptosis and downregulation of Mcl-1 protein levels. Specific knockdown of Mcl-1 gene expression by small interfering RNA also yielded an increase in apoptosis of LNCaP-IL-6+ cells. Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Mcl-1 protein regulation by the endogenous cytokine directly involved the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. Our data support the concept of anti-IL-6 targeted therapy in therapy-resistant prostate cancer.

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Acknowledgements

We gratefully acknowledge G Sierek for expert technical assistance, M Puhr, K Malinowska and Drs G Bartsch and P Berger for their helpful suggestions.

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Authors and Affiliations

  1. Department of Urology, Innsbruck Medical University, Innsbruck, Austria

    I T Cavarretta, H Neuwirt, H Steiner & Z Culig

  2. Department of Medicine, Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

    G Untergasser & H Rumpold

  3. Department of Pathology, Innsbruck Medical University, Innsbruck, Austria

    P L Moser

  4. Centocor R&D, Malvern, PA, USA

    M H Zaki & J A Nemeth

  5. Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria

    D Fuchs

  6. Department of Urology, General Hospital Feldkirch, Feldkirch, Austria

    A Hobisch

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  1. I T Cavarretta
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  2. H Neuwirt
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  3. G Untergasser
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  4. P L Moser
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Correspondence to Z Culig.

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Cavarretta, I., Neuwirt, H., Untergasser, G. et al. The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. Oncogene 26, 2822–2832 (2007). https://doi.org/10.1038/sj.onc.1210097

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