Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers.
Radiation therapy is a major primary treatment option for both localized early stage prostate cancer, and for advanced, regionally un-resectable, cancer. However, around 30% of patients still experience biochemical recurrence after radiation therapy within 10 years. Thus, identification of better biomarkers and new targets are urgently required to improve current therapeutic strategies. The miR-99 family has been shown to play an important role in the regulation of the DNA damage response, via targeting of the SWI/SNF chromatin remodeling factors, SMARCA5 and SMARCD1 in cell line models. In the present study, we have demonstrated that low expression of miR-99a and miR-100 is present in cell populations which are relatively radiation insensitive, for example in prostate cancer stem cells and in castration-resistant prostate cancer. Additionally, treatment of cells with the synthetic glucocorticoid, Dexamethasone resulted in decreased miR-99a and 100 expression, suggesting a new mechanism of miR-99a and 100 regulation in androgen-independent prostate cells. Strikingly, treatment of prostate cells with the glucocorticoid receptor inhibitor, Mifepristone was found to sensitize prostate cells to radiation by increasing the levels of miR-99a and miR-100. These results qualify the miR99 family as markers of radiation sensitivity and as potential therapeutic targets to improve efficiency of radiotherapy.
['Rane|Jayant K|JK|', 'Erb|Holger H H|HH|', 'Nappo|Giovanna|G|', 'Mann|Vincent M|VM|', 'Simms|Matthew S|MS|', 'Collins|Anne T|AT|', 'Visakorpi|Tapio|T|', 'Maitland|Norman J|NJ|']
D045744:Cell Line, Tumor D003907:Dexamethasone D015972:Gene Expression Regulation, Neoplastic D005938:Glucocorticoids D006727:Hormone Antagonists D006801:Humans D008297:Male D035683:MicroRNAs D015735:Mifepristone D014411:Neoplastic Stem Cells D011471:Prostatic Neoplasms D011836:Radiation Tolerance D011965:Receptors, Glucocorticoid
cancer stem cells mifepristone radiotherapy DNA damage repair miRNA