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 lines in 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-3 was 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-3 expression was modified following hypoxic exposure in these cells. NOTCH-3 was 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.
Heliyon. 2016 May 05*** epublish ***
Armelle Meunier, Angela Nilda Flores, Niamh McDermott, Karla Rivera-Figueroa, Antoinette Perry, Thomas Lynch, Kathrine Røe Redalen, Laure Marignol
Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland., Division of International Health, Mount Sinai School of Medicine, New York, USA., Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland., Division of International Health, Mount Sinai School of Medicine, New York, USA., Cancer Biology and Therapeutics Laboratory, Conway Institute, University College Dublin, Ireland., Department of Urology, St James's Hospital, Dublin 8, Ireland., Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Ireland.