Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity.
Fiche publication
Date publication
juillet 2006
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BRONNER Christian
Tous les auteurs :
Un F, Qi C, Prosser M, Wang N, Zhou B, Bronner C, Yen Y
Lien Pubmed
Résumé
BACKGROUND: Ribonucleotide reductase (RR) inhibition by hydroxyurea (HU) causes deoxyribonucleotide (dNTP) depletion, which activates the replication checkpoint, a part of the S-phase checkpoint that responds to DNA damage by inhibiting late origin firing. It also transactivates RR and other genes involved in DNA replication and repair. ICBP90 (overexpressed in breast cancer) is a novel Rb-associating transactivator for the human topoisomerase IIalpha gene and responds to DNA damage-induced checkpoint signaling. MATERIALS AND METHODS: ICBP90 expression was monitored by Western blot. Promoter activity was detected via the luciferase assay and gene silencing via siRNA. Cell death was monitored by the MTT assay. RESULTS: dNTP depletion by HU induced ICBP90, ICBP90 transactivated RR's M2 subunit gene, and ICBP90 induction was necessary for HU-induced M2 accumulation. Blocking the M2 accumulation via anti-ICBP90 siRNA caused greater sensitivity in HU-resistant human cancer. CONCLUSION: A transcriptional intervention strategy is presented through which HU-resistant cancers may be eradicated without dose escalation.
Référence
Anticancer Res. 2006 Jul-Aug;26(4B):2761-7.