The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1
| Autor: | M H Zaki, Hannes Steiner, Dietmar Fuchs, Patrizia Moser, Ilaria T. Cavarretta, Holger Rumpold, Zoran Culig, Hannes Neuwirt, A. Hobisch, Gerold Untergasser, J A Nemeth |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research medicine.medical_treatment Apoptosis Biology medicine.disease_cause Autocrine Communication Targeted therapy Prostate cancer Downregulation and upregulation Genetics medicine Tumor Cells Cultured Humans RNA Small Interfering Protein kinase A Autocrine signalling Molecular Biology Flavonoids Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Interleukin-6 Antibodies Monoclonal Prostatic Neoplasms medicine.disease Neoplasm Proteins Gene Expression Regulation Neoplastic Cytokine Proto-Oncogene Proteins c-bcl-2 Cancer research Disease Progression Myeloid Cell Leukemia Sequence 1 Protein Carcinogenesis |
| Zdroj: | Oncogene. 26(20) |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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