Modulation of 11beta-hydroxysteroid dehydrogenase expression by bombesin: a possible mechanism for glucocorticoid resistance in androgen independent prostate cancer.
Treatment with glucocorticoids is one of a limited number of options for androgen independent prostate cancer. Neuroendocrine differentiation has been shown to contribute to androgen-independent prostate cancer progression. To study the potential link between neuroendocrine differentiation and the glucocorticoid action, we investigated the effects of the product of neuroendocrine differentiation--bombesin on glucocorticoid metabolizing enzymes--11beta-hydroxysteroid dehydrogenases in PC-3 cells. Our Western analysis, RT-PCR, and activity assays demonstrate that while 18-hour exposure to bombesin reduces 11beta-hydroxy-steroid dehydrogenases-1 profiles (activities 25% less, protein level 29% lower, mRNA levels 45% lower), contrarily it increases 11beta-hydroxysteroid dehydrogenases-2 profiles (activities 34%, protein levels 100%, mRNA levels 120%). Blockade bombesin action with bombesin receptor antagonists and the enzyme degrading bombesin prevented these changes, suggesting the observed modulations were bombesin receptor-specific. In addition, bombesin increased the amounts of interleukin-8 and mRNA of vascular endothelial growth factor receptor 2, which were lowered in the presence of cortisol, suggesting that neuropeptide blockade may extend the benefits of glucocorticoids in treating androgen-independent prostate cancer.
Lee
J G
JG
Department of Urology, Urological Oncology laboratory, Weill Medical College of Cornell University, New York, NY 10021, USA.
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Leong
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Nanus
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Shen
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D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D000728:Androgens; D001839:Bombesin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004351:Drug Resistance; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D000728:Androgens; D005938:Glucocorticoids; D016209:Interleukin-8; D012333:RNA, Messenger; D018004:Receptors, Bombesin; D042461:Vascular Endothelial Growth Factor A; D042842:11-beta-Hydroxysteroid Dehydrogenases; D040301:Vascular Endothelial Growth Factor Receptor-2; D001839:Bombesin