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

I. T. Cavarretta, H. Neuwirt, G. Untergasser, P. L. Moser, M. H. Zaki, H. Steiner, H. Rumpold, D. Fuchs, A. Hobisch, J. A. Nemeth, Z. Culig

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2822-2832
Number of pages11
JournalOncogene
Volume26
Issue number20
DOIs
Publication statusPublished - May 3 2007

Keywords

  • Anti-interleukin-6 antibody
  • Apoptosis
  • ERK1/2 mitogen-activated protein kinase
  • Interleukin-6
  • Mcl-1
  • Prostate cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Cavarretta, I. T., Neuwirt, H., Untergasser, G., Moser, P. L., Zaki, M. H., Steiner, H., Rumpold, H., Fuchs, D., Hobisch, A., Nemeth, J. A., & Culig, Z. (2007). The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1. Oncogene, 26(20), 2822-2832. https://doi.org/10.1038/sj.onc.1210097