Hypoxia regulates Notch 3 mRNA and receptor activation in prostate cancer cells
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