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)


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.


Survival Activity Advanced Prostate Cancer Malignant Cell Line Prostate Cancer Model Selective Kinase Inhibitor 
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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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