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.


METHODS
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.
Kooijman
Ron
R
Department of Pharmacology, Medical School, Free University of Brussels, Laarbeeklaan 103, B-1090 Brussels, Belgium. ron.kooijman@vub.ac.be
Himpe
Eddy
E
Potikanond
Saranyapin
S
Coppens
Astrid
A
D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D016207:Cytokines; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D009570:Nitriles; D011994:Recombinant Proteins; C113580:U 0126; D007334:Insulin-Like Growth Factor I; D000077191:Wortmannin