Background: Corticosteroids play important roles in prostate cancer therapeutics. However, their role when combined with enzalutamide remains obscure. Then, we aimed to elucidate the functional and clinical impact of corticosteroids on steroid receptors in androgen receptor (AR)-targeting therapy utilizing enzalutamide. Methods: The therapeutic effect was studied according to concomitant use of corticosteroids in 86 men treated with enzalutamide. The sensitivity to various agents was evaluated using cytotoxicity assays in prostate cancer cells. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction in prostate cancer cells and tissues. Results: The therapeutic effect of enzalutamide was particularly lessened with concomitant treatment with dexamethasone. Consistently, dexamethasone increased cellular resistance to enzalutamide while prednisolone and aldosterone decreased cellular resistance to enzalutamide in prostate cancer cells. Inversely, mineralocorticoid receptor (MR) knockdown augmented the activity of AR signaling and the cellular resistance to enzalutamide. Conclusions: MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.
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