Regulation of interleukin-8 expression in human prostate cancer cells by insulin-like growth factor-I and inflammatory cytokines.

Objective: Since serum IGF-I levels are related to risks of prostate cancer and cytokines like interleukin (IL)-6 and IL-8 have been implicated in prostate cancer progression, we investigated the effects of IGF-I on IL-6 and IL-8 expression in the prostate cancer cell.

Design: In order to address the regulation by IGF-I of cytokine expression in prostate cancer cells we used cell cultures of established androgen dependent (LNCaP) and androgen-independent cell lines (DU-145 and PC-3).

Results: We found that IGF-I stimulates IL-8 mRNA expression and secretion in DU-145 cells, whereas the secretion of IL-6 was hardly affected. IGF-I enhances IL-8 expression in synergy with IL-1beta, but not with tumour necrosis factor (TNF)alpha. Similarly, on IL-8 promoter activity, IGF-I exerted synergistic effects with IL-1beta, but not with TNFalpha. Although IGF-I stimulated the phosphorylation of both Akt (protein kinase B) and extracellular-regulated kinase (ERK), the effect of IGF-I at IL-8 expression was inhibited only by U0126, a pharmacological inhibitor of MAPK/ERK kinase (MEK) and not by inhibition of the upstream activator of Akt, phosphatidylinositol-3 kinase (PI3K).

Conclusions: Our results indicate that IGF-I stimulates IL-8 expression through the MEK-ERK pathway in DU-145 cells, at least in part, by augmentation of transcriptional activity. This finding is in accordance with our observations that IGF-I did not influence cytokine secretion and phosphorylation of ERK in LNCaP or PC-3 cells. It remains to be established whether IL-8 mediates certain effects of IGF-I on prostate cancer cells and whether differential responsiveness of prostate cancer cells to IGF-I relates to certain stages of prostate cancer.