© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 22, 1739-1746,
November 21, 2001
© 2001 Oxford University Press
REPORT |
Potential Mechanism for the Effects of Dexamethasone on Growth of Androgen-Independent Prostate Cancer
Affiliations of authors: K. Nishimura, N. Nonomura, E. Satoh, Y. Harada, M. Nakayama, T. Tokizane, T. Fukui, Y. Ono, H. Inoue, A. Okuyama (Department of Urology), M. Shin, Y. Tsujimoto, H. Takayama, K. Aozasa (Department of Pathology), Graduate School of Medicine, Osaka University, Suita-City, Japan.
Correspondence and reprint requests to: Kazuo Nishimura, M.D., Department of Urology, Graduate School of Medicine, Osaka University, 2–2 Yamadaoka, Suita-City 565–0871 Japan (e-mail: kazu{at}uro.med.osaka-u.ac.jp).
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-
B (NF-B)-dependent cytokine interleukin (IL) 6 (IL-6) is thought to stimulate growth of HRPC. Because dexamethasone interferes with NF-B activation, we determined whether dexamethasone inhibits prostate cancer growth by working through the glucocorticoid receptor (GR) to interfere with NF-B–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-
, and the cytoplasmic NF- inhibitor IB
were determined by western blotting and of IL-6 by enzyme immunoassay. The subcellular localization of NF- 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 IB protein levels and the cytosolic accumulation of NF-B 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-B–IL-6 pathway.
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