TY - JOUR
T1 - Nonhomologous end joining is essential for cellular resistance to the novel antitumor agent, β-lapachone
AU - Bentle, Melissa S.
AU - Reinicke, Kathryn E.
AU - Dong, Ying
AU - Bey, Erik A.
AU - Boothman, David A.
PY - 2007/7/15
Y1 - 2007/7/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=34547125117&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0935
DO - 10.1158/0008-5472.CAN-07-0935
M3 - Article
C2 - 17638905
AN - SCOPUS:34547125117
SN - 0008-5472
VL - 67
SP - 6936
EP - 6945
JO - Cancer research
JF - Cancer research
IS - 14
ER -