Crosstalk between 1,25(OH)2-Vitamin D3 and the growth factors EGF and PDGF-BB: Impact on CYP24A1 expression and cell proliferation

This study explored the signaling interplay between the vitamin D receptor (VDR) and receptor tyrosine kinases (RTKs). Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-BB promotes cell proliferation in normal and cancer cells. At the same time, the active form of vitamin D (1,25(OH) 2 -vitamin D 3 ) inhibits proliferation in some cells. Although EGF receptors (EGFR) and PDGF receptors (PDGFR) activate similar downstream pathways, we found that they interact with VDR signaling in distinct ways. We confirmed that 1,25(OH) 2 -vitamin D 3 induces CYP24A1 gene expression in U2OS, T98G, and U251 cells. We found this to be potentiated when combined with EGF. In contrast, PDGF-BB did not impact 1,25(OH) 2 -vitamin D 3 -induced CYP24A1 expression in U2OS cells. The increase in CYP24A1 expression due to the combined action of EGF and 1,25(OH) 2 -vitamin D 3 was dependent on AKT and ERK1/2 activation. Another VDR-responsive gene, CYP27B1, was unaffected by the addition of EGF, suggesting that EGF may have gene-specific effects on VDR signaling. While PDGF-BB did not influence CYP24A1 expression, 1,25(OH) 2 -vitamin D 3 significantly influenced PDGF-BB-induced receptor phosphorylation and cell proliferation. In summary, we found that EGF, but not PDGF-BB, influenced the expression of the VDR-dependent gene CYP24A1, while 1,25(OH) 2 -vitamin D 3 had an inhibitory effect on PDGFR signaling and proliferation. These findings highlight unique crosstalk between 1,25(OH) 2 -vitamin D 3 signaling and EGF or PDGF-BB. • EGF enhances Vitamin D₃-induced CYP24A1 expression; PDGF-BB has no effect. • EGF and Vitamin D₃ synergistically upregulate CYP24A1 via PI3K/AKT and ERK1/2 pathways. • Vitamin D₃ inhibits PDGF-BB-induced proliferation and PDGFR phosphorylation. • Vitamin D₃ could not suppress EGF-induced cell proliferation.