Differential regulation of bladder cancer growth by various glucocorticoids: Corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity

摘要

Purpose: A synthetic glucocorticoid, dexamethasone, was recently shown to inhibit bladder cancer cell invasion and metastasis through the glucocorticoid receptor (GR) pathway but increased cell proliferation via inhibiting apoptosis particularly induced by cisplatin. Therefore, comedication with dexamethasone in bladder cancer patients may lead to unfavorable outcomes such as chemoresistance. We here look for any glucocorticoids with inhibitory effects on tumor cell invasion yet inhibitory or at least no stimulatory effects on cell viability. Methods: The effects of 10 glucocorticoids on cell viability were first assessed in three bladder cancer lines. Selected compounds were further assessed for their ability in cell viability and apoptosis, with or without cisplatin, as well as in cell invasion. Results: Most of the compounds (hydrocortisone, betamethasone, flumethasone, triamcinolone, budesonide, fluticasone propionate, and fludrocortisone acetate) increased GR-positive cell growth, which was similar to or even stronger than the effect of dexamethasone. Nonetheless, two glucocorticoids (corticosterone, prednisone) showed only marginal effects on cell growth of all the lines tested. They did not significantly reduce the effects of cisplatin on cell proliferation or cisplatin-induced apoptosis. Conversely, corticosterone, prednisone, and dexamethasone similarly inhibited cell invasion and expression of related genes, including MMP-9, VEGF, and IL-6, in GR-positive lines. Conclusion: Corticosterone and prednisone are suggested to have the potential of being harmless, in contrast to dexamethasone, without promoting cell proliferation or inhibiting cytotoxic activity of cisplatin, yet beneficial to bladder cancer patients via suppressing tumor invasion. Our results are thus useful in improving chemotherapy regimens, including optimal glucocorticoids, for urothelial carcinoma.