Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells

J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):37-46. doi: 10.1016/j.jsbmb.2005.06.011. Epub 2005 Aug 1.

Abstract

We have previously shown that concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D) that induce G(0)/G(1) cell cycle arrest in androgen-dependent LNCaP prostate cancer cells also decrease expression of c-Myc, a proto-oncogene that stimulates progression from G(1) to S phase of the cell cycle. Since both c-Myc expression and cell cycle progression are regulated by tyrosine kinase activation, we examined the ability of 1,25D to alter tyrosine kinase signaling in LNCaP cells and the androgen-independent LNCaP C81 (C81 LN) cell line. 1,25D selectively reduced protein tyrosine phosphorylation within both the LNCaP and C81 LN cells. This reduction in tyrosine kinase signaling appears to result from elevated levels of cellular prostatic acid phosphatase (PAcP). Western blots and biochemical assays revealed 1,25D increases the level of active PAcP in both cell lines. In addition, 1,25D decreased tyrosine phosphorylation of HER-2, an EGFR family member inactivated by PAcP, and the HER-2 downstream adaptor protein p52 Shc in C81 LN cells. Inhibition of HER-2 signaling by AG825 reduces growth of C81 LN cells and the parental LNCaP cells. These data therefore suggest that 1,25D-mediated decreases in LNCaP and C81 LN cell growth are in part due to decreases in tyrosine kinase signaling that result from up-regulation of PAcP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Phosphatase
  • Calcitriol / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Down-Regulation
  • Humans
  • Male
  • Oligopeptides / biosynthesis
  • Oligopeptides / metabolism
  • Phosphotyrosine / analysis
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / enzymology*
  • Prostatic Neoplasms / metabolism
  • Protein Tyrosine Phosphatases / metabolism*
  • Proto-Oncogene Mas
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Calcitriol / agonists*
  • Signal Transduction / drug effects*
  • Vitamin D / metabolism
  • Vitamin D / pharmacology
  • cdc25 Phosphatases / biosynthesis

Substances

  • MAS1 protein, human
  • Oligopeptides
  • Proto-Oncogene Mas
  • Receptors, Calcitriol
  • protein C activator peptide
  • Vitamin D
  • Phosphotyrosine
  • Receptor, ErbB-2
  • Acid Phosphatase
  • prostatic acid phosphatase
  • CDC25A protein, human
  • Protein Tyrosine Phosphatases
  • cdc25 Phosphatases
  • Calcitriol