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

Julia B Cordero1, Mario Cozzolino, Yan Lu

  • 1Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The Journal of Biological Chemistry
|August 16, 2002
PubMed

Insights

1,25(OH)(2)D(3) (calcitriol) inhibits cancer cell growth by disrupting the TGF-alpha/EGFR signaling pathway. This vitamin D3 metabolite alters epidermal growth factor receptor (EGFR) localization and reduces downstream signaling, impacting cell proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • The antiproliferative effects of 1,25(OH)(2)D(3) (calcitriol) are established but not fully understood at the molecular level.
  • Tumor and hyperplastic tissue growth driven by co-expressed epidermal growth factor receptor (EGFR) and transforming growth factor-alpha (TGF-alpha) are sensitive to 1,25(OH)(2)D(3).

Purpose of the Study:

  • To investigate the hypothesis that 1,25(OH)(2)D(3) modulates the TGF-alpha/EGFR autocrine growth loop.
  • To elucidate the molecular mechanisms by which 1,25(OH)(2)D(3) regulates EGFR-mediated growth signals.

Main Methods:

  • Utilized human epidermoid A431 cells, characterized by EGFR and TGF-alpha overexpression driving autocrine signaling.
  • Assessed the effects of 1,25(OH)(2)D(3) on A431 cell proliferation, EGFR and TGF-alpha cellular localization, EGFR and ERK1/2 phosphorylation, and EGFR nuclear translocation.

Main Results:

  • 1,25(OH)(2)D(3) significantly inhibited both autocrine and epidermal growth factor (EGF)-induced A431 cell proliferation.
  • Observed alterations in the cellular distribution of TGF-alpha and EGFR, alongside inhibition of ligand-dependent EGFR and ERK1/2 phosphorylation.
  • Demonstrated impaired nuclear translocation of activated EGFR, reduced binding to AT-rich DNA sequences, and decreased cyclin D1 promoter transcriptional activity.

Conclusions:

  • 1,25(OH)(2)D(3) effectively down-regulates EGFR growth signaling by altering EGFR membrane trafficking.
  • The findings reveal a novel mechanism for the antiproliferative action of 1,25(OH)(2)D(3) involving the disruption of the EGFR signaling pathway.

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