Kazuo Nishimura, Kazuo Nishimura, Norio Nonomura, Eiichi Satoh, Yasunori Harada, Masashi Nakayama, Takashi Tokizane, Tatsunari Fukui, Yutaka Ono, Hitoshi Inoue, Masaru Shin, Yuichi Tsujimoto, Hitoshi Takayama, Katsuyuki Aozasa, Akihiko Okuyama
Journal of the National Cancer Institute 2001年11月21日
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-κB, and the cytoplasmic NF-κB inhibitor IκBα were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF-κB 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<.001; PC-3 cells, P = .009). Dexamethasone increased IκBα protein levels and the cytosolic accumulation of NF-κB 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-κB-IL-6 pathway.