title: Mcl-1 is regulated by IL-6 and mediates the survival activity of the cytokine in a model of late stage prostate carcinoma.
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.
authors.affiliation: Department of Urology, Innsbruck Medical University, Anichstrasse, Innsbruck, Austria.
authors.forename: Ilaria Teresa
authors.initials: IT
authors.lastname: Cavarretta
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Zaki
authors.forename: Hannes
authors.initials: H
authors.lastname: Steiner
authors.forename: Alfred
authors.initials: A
authors.lastname: Hobisch
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nemeth
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C504234:siltuximab