Nonhomologous end joining is essential for cellular resistance to the novel antitumor agent, β-lapachone

Melissa S. Bentle, Kathryn E. Reinicke, Ying Dong, Erik A. Bey, David A. Boothman

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Commonly used antitumor agents, such as DNA topoisomerase I/II poisons, kill cancer cells by creating nonrepairable DNA double-strand breaks (DSBs).T o repair DSBs, error-free homologous recombination (HR), and/or error-prone nonhomologous end joining (NHEJ) are activated. These processes involve the phosphatidylinositol 3′-kinase-related kinase family of serine/threonine enzymes: ataxia telangiectasia mutated (ATM), ATM- and Rad3-related for HR, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) for NHEJ. Alterations in these repair processes can cause drug/radiation resistance and increased genomic instability. β-Lapachone (β-lap; also known as ARQ 501), currently in phase II clinical trials for the treatment of pancreatic cancer, causes a novel caspase- and p53-independent cell death in cancer cells overexpressing NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 catalyzes a futile oxidoreduction of β-lap leading to reactive oxygen species generation, DNA breaks, γ-H2AX foci formation, and hyperactivation of poly(ADP-ribose) polymerase-1, which is required for cell death. Here, we report that β-lap exposure results in NQO1-dependent activation of the MRE11-Rad50-Nbs-1 complex. In addition, ATM serine 1981, DNA-PKcs threonine 2609, and Chk1 serine 345 phosphorylation were noted; indicative of simultaneous HR and NHEJ activation. However, inhibition of NHEJ, but not HR, by genetic or chemical means potentiated β-lap lethality. These studies give insight into the mechanism by which β-lap radiosensitizes cancer cells and suggest that NHEJ is a potent target for enhancing the therapeutic efficacy of β-lap alone or in combination with other agents in cancer cells that express elevated NQO1 levels.

Original languageEnglish (US)
Pages (from-to)6936-6945
Number of pages10
JournalCancer Research
Volume67
Issue number14
DOIs
StatePublished - Jul 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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