Contrary Regulation of Bladder Cancer Cell Proliferation and Invasion by Dexamethasone-Mediated Glucocorticoid Receptor Signals
Menée in vitro et à l'aide de xénogreffes, cette étude montre que la dexaméthasone, une hormone glucocorticoïde souvent prescrite pour réduire la toxicité d'une chimiothérapie chez les patients atteints d'un cancer avancé de la vessie, est susceptible de favoriser la prolifération cellulaire en inhibant l'apoptose
In patients with advanced bladder cancer, glucocorticoids are frequently given to reduce acute toxicity, particularly hyperemesis, during chemotherapy, as well as to improve cachectic conditions. However, it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor (GR) pathway. GR expression was first investigated in human bladder cancer lines and tissue microarrays. Then, the effects of dexamethasone on GR transcription, cell proliferation, apoptosis/cell-cycle, and invasion were examined in bladder cancer lines. Finally, mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression. All the cell lines and tissues examined were found to express GR. Dexamethasone increased GR-mediated reporter activity and cell proliferation, and inhibited apoptosis in the presence or absence of cisplatin. In contrast, dexamethasone suppressed cell invasion, the expression of its related genes (MMP-2/MMP-9, IL-6, VEGF), and the activity of MMP-2/MMP-9, and also induced mesenchymal-to-epithelial transition. Additionally, dexamethasone increased IκBα protein levels and cytosolic accumulation of NF-κB. In xenograft-bearing mice, dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites, suggestive of peritoneal dissemination of tumor cells, and actual metastasis. In all these assays, dexamethasone effects were abolished by a GR antagonist or GR knock-down via RNA interference. Thus, GR activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis. These results may provide a basis of developing improved chemotherapy regimens, including or excluding GR agonists/antagonists, for urothelial carcinoma.
http://mct.aacrjournals.org/content/early/2012/09/29/1535-7163.MCT-12-0621.abstract