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

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

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.

Original languageEnglish
Title of host publicationAdvances in Experimental Medicine and Biology
Pages547-555
Number of pages9
Volume617
DOIs
Publication statusPublished - 2008

Publication series

NameAdvances in Experimental Medicine and Biology
Volume617
ISSN (Print)00652598

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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