S-phase arrest and apoptosis induced in normal mammary epithelial cells by a novel retinoid

Cancer Res. 2000 Apr 1;60(7):2025-32.

Abstract

The addition of all-trans-retinoic acid has been found to mediate a G1 cell cycle phase arrest but not apoptosis in normal mammary epithelial cells. We have now found that addition of the novel retinoid 6-[3-(1-adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which appears to function through a pathway independent of retinoic acid nuclear receptors, results in an S-phase arrest that is preceded by a 4-fold elevation in the levels of the cyclin-cyclin dependent kinase (cdk) inhibitor p21WAF1/CIP1. Failure to inhibit E2F-1 activation of genes through its phosphorylation by the cyclin cdk2 kinase has been shown to result in S-phase arrest and apoptosis in a number of cell types. Although exposure of the normal mammary cells to CD437 does not result in modulation of cyclin A or cdk2 levels, an increase in E2F-1 levels and a marked inhibition of cyclin A/cdk2 kinase activity are observed. Exposure to CD437 results in enhanced E2F-1 binding to its DNA consensus sequences and transcriptional activity during S phase. We hypothesize that this enhanced E2F-1 transcriptional activity results in S-phase arrest and subsequent apoptosis that has been observed in other systems.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Breast / cytology
  • Breast / drug effects*
  • Breast / physiology
  • Cell Cycle / drug effects*
  • Cell Division / drug effects
  • Cell Line
  • Cyclin-Dependent Kinases / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / physiology
  • Female
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Receptors, Retinoic Acid / physiology
  • Retinoic Acid Receptor alpha
  • Retinoids / pharmacology*
  • S Phase / drug effects
  • Transfection
  • beta-Galactosidase / genetics

Substances

  • Antineoplastic Agents
  • CD 437
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoids
  • retinoic acid receptor beta
  • retinoic acid receptor gamma
  • Luciferases
  • Cyclin-Dependent Kinases
  • beta-Galactosidase