Epidermal growth factor stimulates 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression via the ErbB-2 pathway in human breast adenocarcinoma cells

Biochem Biophys Res Commun. 1999 Jul 14;260(3):699-706. doi: 10.1006/bbrc.1999.0945.

Abstract

HMG-CoA reductase is the key enzyme for the biosynthesis of isoprenoid compounds essential for cell growth and differentiation. Its tyrosine kinase-dependent modulation has recently been suggested and described in the ErbB-2 overexpressing cell line SKBR-3 [Asslan et al. (1998) Biochem. J. 330, 241-246]. Epidermal growth factor (EGF) increased the HMG-CoA reductase activity, protein, and mRNA levels only in ErbB-2-expressing cells (SKBR-3 and MCF-7) but not in MDA-MB-468 cells that do not express ErbB-2 even though their EGF receptor was efficiently phosphorylated. Tyrphostin AG 879, a specific inhibitor of ErbB-2 tyrosine kinase activity, decreased HMG-CoA reductase activity only in cells that expressed ErbB-2. A functional EGF receptor appeared to be necessary since its inhibition by the specific tyrphostin AG 1478 abolished the EGF effects. Phosphatidylinositol 3-kinase (PI 3-kinase) might be a crucial enzyme in the signaling pathway since the specific inhibitor, LY 294002, was shown to inhibit HMG-CoA reductase activity and to completely abolish the stimulation by EGF in SKBR-3 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Chromones / pharmacology
  • Epidermal Growth Factor / antagonists & inhibitors
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Quinazolines
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured
  • Tyrphostins / pharmacology

Substances

  • AG-879
  • Chromones
  • Flavonoids
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinazolines
  • Tyrphostins
  • RTKI cpd
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Epidermal Growth Factor
  • Hydroxymethylglutaryl CoA Reductases
  • Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one