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Mcl-1 is Regulated by IL-6 and Mediates the Survival Activity of the Cytokine in a Model of Late Stage Prostate Carcinoma

  • Ilaria Teresa Cavarretta
  • Hannes Neuwirt
  • Mohamed H. Zaki
  • Hannes Steiner
  • Alfred Hobisch
  • Jeffrey A. Nemeth
  • Zoran Culig
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Summary

The proinflammatory cytokine interleukin-6 (IL-6) has been considered a positive growth factor in late stage prostate cancer (PC) cells and a potential target for therapeutic interference. We studied the effects of inhibition of IL-6 in LNCaP-IL6+ cells, a model system for advanced PC, which produce IL-6. By using the chimeric anti-IL-6 antibody, CNTO 328, we showed that the autocrine IL-6 loop is responsible for decreased sensitivity of LNCaP-IL-6+ cells to die by apoptosis. Dysregulation of Bcl-2 family members could be implicated in the acquisition of resistance to apoptosis in malignant cell lines. Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of this family that is overexpressed in the IL-6 selected cells compared with control. Specific knock-down of Mcl-1 gene expression by siRNA yielded an increase in apoptosis of LNCaP-IL-6+ cells. Interestingly, inactivation of IL-6 autocrine loop was not able to increase apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Finally, using selective kinase inhibitors we provide evidence for the involvement of p38 and ERK1/2 mitogen-activated protein kinases pathways in the IL-6-mediated regulation of Mcl-1. In conclusion, these data suggest that endogenous IL-6 acts as an antiapoptotic factor in LNCaP-IL-6+ cells and that Mcl-1 is critical for its survival activity. CNTO 328, in our experimental conditions, is able to render LNCaP-IL-6+ cells more sensitive to apoptosis. These data support the concept of anti-IL-6 therapy in human PC.

Keywords

Survival Activity Advanced Prostate Cancer Malignant Cell Line Prostate Cancer Model Selective Kinase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer 2008

Authors and Affiliations

  • Ilaria Teresa Cavarretta
    • 1
  • Hannes Neuwirt
  • Mohamed H. Zaki
  • Hannes Steiner
  • Alfred Hobisch
  • Jeffrey A. Nemeth
  • Zoran Culig
    • 2
  1. 1.Department of UrologyInnsbruck Medical UniversityInnsbruckAustria
  2. 2.Department of UrologyUniversity of InnsbruckInnsbruckAustria

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