title: Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers.
abstract: 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.
authors.affiliation: The Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, YO10 5DD, UK.|Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Rayne Institute, London, SE5 9NU, UK.
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Rane
authors.affiliation: The Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, YO10 5DD, UK.
authors.forename: Holger H H
authors.initials: HH
authors.lastname: Erb
authors.affiliation: The Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, YO10 5DD, UK.|Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Department of Experimental and Clinical Medicine, Magna Græcia University, 88100, Catanzaro, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Nappo
authors.affiliation: Hull York Medical School, University of Hull, Hull, East Yorkshire, HU6 7RX, UK.|Department of Urology, Castle Hill Hospital, Cottingham, East Yorkshire, HU16 5JQ, UK.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Mann
authors.affiliation: Hull York Medical School, University of Hull, Hull, East Yorkshire, HU6 7RX, UK.|Department of Urology, Castle Hill Hospital, Cottingham, East Yorkshire, HU16 5JQ, UK.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Simms
authors.affiliation: The Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, YO10 5DD, UK.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Collins
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere and Tampere University Hospital, Tampere, 33520 Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: The Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, YO10 5DD, UK.|Hull York Medical School, University of Hull, Hull, East Yorkshire, HU6 7RX, UK.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
mesh_terms: D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*
chemical_list: D005938:Glucocorticoids; D006727:Hormone Antagonists; C544266:MIRN100 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone
keywords: DNA damage repair; cancer stem cells; miRNA; mifepristone; radiotherapy