1. ¹Department of Urology, Innsbruck Medical University, Innsbruck, Austria
2. ²Department of Medicine, Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria
3. ³Department of Pathology, Innsbruck Medical University, Innsbruck, Austria
4. ⁴Centocor R&D, Malvern, PA, USA
5. ⁵Biocenter, Division of Biological Chemistry, Innsbruck Medical University, Innsbruck, Austria
6. ⁶Department of Urology, General Hospital Feldkirch, Feldkirch, Austria

Correspondence: Dr Z Culig, Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: zoran.culig@uibk.ac.at

Received 15 May 2006; Revised 7 September 2006; Accepted 28 September 2006; Published online 30 October 2006.

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.