New insights into the molecular mechanisms underlying sensitivity/ resistance to the atypical retinoid ST1926 in acute myeloid leukaemia cells: The role of histone H2A.Z, cAMP-dependent protein kinase A and the proteasome

Maddalena Fratelli, James Neil Fisher, Gabriela Paroni, Angela Maria Di Francesco, Filomena Pierri, Claudio Pisano, Klaus Godl, Sandra Marx, Andreas Tebbe, Claudia Valli, Maurizio Gianni, Matteo Stravalaci, Marco Gobbi, Mineko Terao, Enrico Garattini

Research output: Contribution to journalArticlepeer-review

Abstract

ST1926 is an atypical retinoid and a promising anti-tumour agent with selective apoptotic activity on the leukaemic blast. The anti-tumour activity of the compound has been associated with its capacity to induce DNA double stranded breaks. Target profiling by affinity chromatography coupled to mass spectrometry led to the identification of histone H2A.Z as a protein capable of binding ST1926 specifically. The result was confirmed by studies involving Surface Plasmon Resonance (SPR). This indicates that H2A.Z is a primary target of ST1926 and links the perturbations of the histone pathway observed by microarray analysis to the DNA damage and apoptotic responses caused by the atypical retinoid. Comparison of the whole-genome gene-expression profiles of the ST1926-sensitive NB4 and the ST1926-resistant NB4.437r cell lines demonstrated differential expression of numerous genes. Network analysis of the data indicated enrichment of the cellular pathways controlling cAMP (cyclic adenosinemonophosphate)-dependent signal transduction, proteasome-dependent protein degradation and nuclear histones in NB4.437r cells. Pharmacological inhibition of cAMP-dependent protein kinase A with H89 partially reverted resistance of NB4.437r cells to ST1926. Conversely, inhibition of the proteasome with MG132 or bortezomib blocked the apoptotic response afforded by ST1926 in the NB4 cell line. This last effect was associated with a dramatic reduction in the DNA damage caused by the atypical retinoid. The results corroborate the idea that DNA damage is an important determinant of ST1926 apoptotic activity. More importantly, they demonstrate a proactive role of the proteasome in the DNA damaging and ensuing apoptotic response observed upon the challenge of acute myeloid leukaemia cells with ST1926.

Original languageEnglish
Pages (from-to)1491-1500
Number of pages10
JournalEuropean Journal of Cancer
Volume49
Issue number6
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Acute myeloid leukaemia
  • Apoptosis
  • Atypical retinoids
  • Cytotoxicity
  • DNA damage
  • Retinoic acid
  • Retinoids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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