title: Hypoxia regulates Notch-3 mRNA and receptor activation in prostate cancer cells.
abstract: The Notch-3 receptor is a recognized key regulator of vascular responses and is increasingly associated with tumorigenesis. Hypoxia-inducible factors activate specific signaling pathways such as Notch in a number of cellular models. This study aimed to evaluate the regulation of Notch-3 by hypoxia in prostate cancer cells. Notch-3 gene and protein expression was established in a panel of aerobic and hypoxic prostate cell linesin vitro, the CWR22 xenograft model and RNA extracted from low grade (Gleason score < = 6); high grade (Gleason score > = 7); non-hypoxic (low HIF, low VEGF); hypoxic (high HIF, high VEGF) patient FFPE specimens.NOTCH-3was upregulated in PC3 (3-fold), 22Rv1 (4.1-fold) and DU145 (3.8-fold) but downregulated in LnCaP (12-fold) compared to the normal cell lines.NOTCH-3expression was modified following hypoxic exposure in these cells.NOTCH-3was upregulated (2.2-fold) in higher grade and hypoxic tumors, when compared to benign and aerobic pools. In the CWR22 xenograft model, Notch-3 expression was restored in castrate resistant tumors. Nuclear translocation of the Notch-3 intracellular domain was no longer detected following exposure of cells to hypoxia but not associated with a change in expression of HES-1. Our data further identifies Notch-3 as a potentially key hypoxic-responsive member of the Notch pathway in prostate tumorigenesis.
authors.affiliation: Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland.
authors.forename: Armelle
authors.initials: A
authors.lastname: Meunier
authors.affiliation: Division of International Health, Mount Sinai School of Medicine, New York, USA.
authors.forename: Victoria Anastasia
authors.initials: VA
authors.lastname: Belle
authors.affiliation: Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: McDermott
authors.affiliation: Division of International Health, Mount Sinai School of Medicine, New York, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Rivera-Figueroa
authors.affiliation: Cancer Biology and Therapeutics Laboratory, Conway Institute, University College Dublin, Ireland.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Perry
authors.affiliation: Department of Urology, St James's Hospital, Dublin 8, Ireland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lynch
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Kathrine Røe
authors.initials: KR
authors.lastname: Redalen
authors.affiliation: Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland.
authors.forename: Laure
authors.initials: L
authors.lastname: Marignol
keywords: Cell biology; Medicine