Modulation of 11β-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 - 11β-hydroxysteroid dehydrogenases in PC-3 cells. Our Western analysis, RT-PCR, and activity assays demonstrate that while 18-hour exposure to bombesin reduces 11β-hydroxysteroid dehydrogenases-1 profiles (activities 25% less, protein level 29% lower, mRNA levels 45% lower), contrarily it increases 11β-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