1,25-dihydroxyvitamin D down-regulates cell membrane growth- and nuclear growth-promoting signals by the epidermal growth factor receptor

1,25(OH)(2)D-3 antiproliferative properties are widely known. However, the molecular bases of these properties are only partially elucidated. Since 1,25(OH)(2)D-3 effectively arrests growth in many tumors and hyperplastic tissues whose growth is driven by co-expression of EGFR and its ligand TGF-alpha, it was hypothesized that 1,25(OH)(2)D-3 could affect the TGF-alpha/EGFR-autocrine growth loop. This study examined 1,25(OH)(2)D-3 regulation of EGFR-growth signals, using human epidermoid A431 cells, in which the overexpression of EGFR and TGF-a constitute the major autocrine mitogenic signal. 1,25(OH)(2)D-3 inhibited autocrine and EGF-induced A431 cell proliferation. Furthermore, 1,25(OH)(2)D-3 changed the cellular localization of both TGF-alpha and EGFR and inhibited ligand-dependent phosphorylation of EGFR and ERK1/2. In addition, 1,25(OH)(2)D-3 impaired autocrine and EGF-induced nuclear translocation of activated EGFR and, consequently, its binding to AT-rich DNA sequences and transcriptional activation of the cyclin D1 promoter. These results demonstrate that 1,25(OH)(2)D-3 alters EGFR membrane trafficking and down-regulates EGFR growth signaling.