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 (HRPC), but the mechanisms responsible for its effects are unknown. The nuclear factor-κB (NF-κB)-dependent cytokine interleukin (IL) 6 (IL-6) is thought to stimulate growth of HRPC. Because dexamethasone interferes with NF-KB activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-KB-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-KB, and the cytoplasmic NF-KB inhibitor IκBα 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 pg/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 IκBα protein levels and the cytosolic accumulation of NF-KB 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 (≥30% GR-positive cells). Conclusion: Dexamethasone inhibited the growth of GR-positive cancers, possibly through the disruption of the NF-KB-IL-6 pathway.