Expression of interleukin‐6 is downregulated by 17‐(allylamino)‐17‐demethoxygeldanamycin in human prostatic carcinoma cells 1

Aim: Interleukin‐6 (IL‐6) is a pleiotropic cytokine that is associated with tumor metastasis and prostate cancer. We evaluated the mechanism and effect of 17‐(allylamino)‐17‐demethoxygeldanamycin (17AAG), a novel inhibitor of heat shock protein 90 (Hsp90), on the IL‐6 gene expression in human prostatic carcinoma (PC‐3) cells. Methods: Quantitative IL‐6 and IL‐6 receptor (IL‐6R) expressions were assessed using RT‐PCR. The deregulation of 17AAG and phor‐bol 12‐myristate 13‐acetate (PMA) on the IL‐6 gene was determined by ELISA and transient gene expression assays using an IL‐6 reporter vector. Results: Although the IL‐6R is ubiquitously expressed by prostatic epithelium cells, the IL‐6 expression is only found in advanced prostatic carcinoma cells, such as PC‐3 and DU145. Further studies using RT‐PCR indicated that 17AAG downregulated the gene expression of IL‐6. ELISA and the transient gene expression assay revealed that 17AAG blocked the stimulation of PMA of IL‐6 gene expression in PC‐3 cells. The PMA‐induced IL‐6 gene expression is dependent on the NF‐κB response element. However, the effect of 17AAG appears to be mediated via a region located at ‐149 to +8 bp upstream of the transcriptional starting site of the IL‐6 gene, and might not be through the NF‐κB signaling pathway. Conclusion: The present study reveals that IL‐6 is transcriptionally downregulated in human prostatic carcinoma cells in response to 17AAG. This result suggests the presence of a novel Hsp90 mediation pathway that is involved in the deregulation on the transcription of the human IL‐6 gene in human prostate cancer.