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-alpha 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.
Cordero
Julia B
JB
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cozzolino
Mario
M
Lu
Yan
Y
Vidal
Marcos
M
Slatopolsky
Eduardo
E
Stahl
Philip D
PD
Barbieri
M Alejandro
MA
Dusso
Adriana
A
D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D002117:Calcitriol