Androgens block interleukin-1 beta-induced promatrilysin expression in prostate carcinoma cells.
BACKGROUND
We have shown previously that interleukin (IL) -1 beta- and IL-6-induced promatrilysin expression is mediated by an indirect pathway that requires NF kappa B-dependent synthesis of IL-6 and STAT3 signaling. We now demonstrate that IL-1 beta-induced but not IL-6-induced promatrilysin expression can be blocked by androgens in the prostate carcinoma cell line LNCaP (lymph node-derived carcinoma cells of the prostate).


METHODS
By using enzyme-linked immunosorbent assay analyses, promatrilysin was measured in LNCaP cells stimulated with IL-1 beta or IL-6 LNCaP-treated cells pretreated with testosterone. In addition, promatrilysin message was measured by using Northern analyses after IL-6-treated cells pretreated with testosterone.


RESULTS
In LNCaP treated with testosterone before IL-1 beta stimulation induced promatrilysin expression was completely abrogated. Furthermore, testosterone completely abrogated NF kappa B transactivation activity and induction of IL-6 protein expression and mRNA. Testosterone and 5 alpha-dihydrotestosterone did not have an inhibitory effect on IL-6-induced promatrilysin expression. Testosterone also had no effect on basal promatrilysin expression or basal NF kappa B transactivation activity.


CONCLUSIONS
From these data, we conclude that testosterone blocks IL-1 beta-induced promatrilysin expression by inhibition of NF kappa B transactivation activity, which in turn, blocks IL-6 expression. These data suggest a mechanism in vivo by which invasive and metastatic prostatic carcinoma cell clones refractory to hormone ablation therapy may develop after chemical or surgical castration. Furthermore, these data suggest that, perhaps, upstream targets such as the cytokines IL-1 beta and IL-6 may provide alternative drug targets for inhibiting prostate cancer progression.
Stratton
M Suzanne
MS
Department of Radiation Oncology, Arizona Cancer Center, Tucson, Arizona 85724, USA.
Greenstein
Benjamin
B
Udayakumar
Thirupandiyur S
TS
Nagle
Raymond B
RB
Bowden
G Timothy
GT
D015152:Blotting, Northern; D002277:Carcinoma / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004792:Enzyme Precursors / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction; D013739:Testosterone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D007375:Interleukin-1; D015850:Interleukin-6; D013739:Testosterone; D008666:Metalloendopeptidases; C099583:promatrilysin