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-κB activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-κB–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-κβ, and the cytoplasmic NF-κβ inhibitor IκBα were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF-κβ was analyzed by immunofluorescence. The effects of dexamethasone (thrice weekly injections of 1 μg/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