Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer

Background: Dexamethasone, a synthetic glucocorticoid, has clinical benefit in patients with hormone-refractory prostate cancer (HR-PC), but the mechanisms responsible for its effects are unknown. The nuclear factor-kappaB (NF-kappaB)-dependent cytokine interleukin (IL) 6 (IL-6) is thought to stimulate growth of HRPC. Because dexamethasone interferes with NF-kappaB activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-kappaB-IL-6 pathway. Methods: Three human prostate cancer cell lines (DU145, PC-3, and LNCaP) were assessed for GR expression and responsiveness to dexamethasone. Levels of GR, NF-kappaB, and the cytoplasmic NF-kappaB inhibitor I kappaB alpha were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF-KB was analyzed by immunofluorescence. The effects of dexamethasone (thrice weekly injections of 1 mug/mouse) on DU145 xenografts in nude and severe combined immunodeficient (SCID) mice were evaluated. GR expression in human prostate cancers was assessed by immunohistochemistry. All statistical tests were two-sided. Results: Dexamethasone dose dependently decreased GR levels and inhibited the growth of DU145 and PC-3 but not LNCaP cells (DU145 cells, P < .001; PC-3 cells, P = .009). Dexamethasone increased I kappaB alpha protein levels and the cytosolic accumulation of NF-kappaB in DU145 cells and decreased secreted IL-6 levels to 37 pg/mL (95% confidence interval [CI] = 33 pg/mL to 41 pg/mL), compared with 164 pg/mL (95% CI = 162 pg/mL to 166 pg/mL) secreted by ethanol-treated control cells. Dexamethasone inhibited the growth of DU145 xenografts in nude (P = .006) and SCID (P = .026) mice without affecting GR levels. Eight of 16 human prostate cancers expressed GR at high levels (greater than or equal to 30% GR-positive cells). Conclusion: Dexamethasone inhibited the growth of GR-positive cancers, possibly through the disruption of the NF-kappaB-IL-6 pathway.