Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases

M. Giannǐ, I. Ponzanelli, L. Mologni, U. Reichert, A. Rambaldi, M. Terao, E. Garattini

Research output: Contribution to journalArticlepeer-review

Abstract

In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARα-selective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARβ agonist and an anti-AP1 retinoid have very limited activity, ATRA- and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARα. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD.

Original languageEnglish
Pages (from-to)447-460
Number of pages14
JournalCell Death and Differentiation
Volume7
Issue number5
Publication statusPublished - May 2000

Keywords

  • APL
  • ATRA
  • Caspase
  • Retinoids

ASJC Scopus subject areas

  • Cell Biology

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