Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity

Frank Un, Christina Qi, Megan Prosser, Norby Wang, Bingsen Zhou, Christian Bronner, Yun Yen

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 IIa 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.

Original languageEnglish
Pages (from-to)2761-2767
Number of pages7
JournalAnticancer Research
Volume26
Issue number4 B
Publication statusPublished - Jul 1 2006
Externally publishedYes

Fingerprint

Hydroxyurea
Ribonucleotide Reductases
Small Interfering RNA
DNA Damage
S Phase Cell Cycle Checkpoints
Deoxyribonucleotides
Genes
Trans-Activators
Gene Silencing
Luciferases
DNA Replication
DNA Repair
Neoplasms
Cell Death
Western Blotting
ribonucleotide reductase M2
Breast Neoplasms

Keywords

  • Checkpoint
  • Hydroxyurea
  • ICBP90
  • Lytic path
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity. / Un, Frank; Qi, Christina; Prosser, Megan; Wang, Norby; Zhou, Bingsen; Bronner, Christian; Yen, Yun.

In: Anticancer Research, Vol. 26, No. 4 B, 01.07.2006, p. 2761-2767.

Research output: Contribution to journalArticle

Un, Frank ; Qi, Christina ; Prosser, Megan ; Wang, Norby ; Zhou, Bingsen ; Bronner, Christian ; Yen, Yun. / Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity. In: Anticancer Research. 2006 ; Vol. 26, No. 4 B. pp. 2761-2767.
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AU - Bronner, Christian

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