The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining

Kriegs, Malte; Kasten-Pisula, Ulla; Rieckmann, Thorsten; Holst, Katharina; Saker, Jarob; Dahm-Daphi, Jochen; Dikomey, Ekkehard

doi:10.1016/j.dnarep.2010.05.005

Cited by 108 publications

(74 citation statements)

References 40 publications

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“…This is surprising, as both ATO and inhibition of EGFR and its downstream signals have been shown to result in compromised DNA repair processes (22,(34)(35)(36)(37). Interestingly, we could not detect an enhanced generation of ROS in the drug combination despite synergistic induction of DNA DSBs and subsequent phosphorylation of H2AX.…”

Section: Discussioncontrasting

confidence: 46%

“…Notably, besides multiple other functions, the EGFR pathway has been recently shown to be involved in the regulation of DNA DSB repair by positive regulation of both the homologous recombination as well as the nonhomologous end-joining (22,37). Thus, activation of EGFR resulted in a decreased number of residual DNA DSBs, whereas the number of H2AX-positive DSB foci was clearly increased when EGFR was blocked by erlotinib in A549 and other lung cancer cell lines (22,34). Moreover, erlotinib also attenuated DNA damageinduced Rad51 foci and resulted in cytoplasmic retention of BRCA1 (37), both essential components of the DSB repair machinery.…”

Section: Discussionmentioning

confidence: 99%

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Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G 2 -M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFRmediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR. Mol Cancer Ther; 12(6); 1073-84. Ó2013 AACR.

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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“…An early step in DNA DSB repair by NHEJ is the binding of the serine/threonine kinase, DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) to the damaged DNA ends, followed by its autophosphorylation. There is also substantial evidence that EGFR translocates to the nucleus in response to DNA DSB damage, and forms part of the DNA-PK-dependent repair process (Dittmann, et al 2005;Kriegs, et al 2010).…”

Section: Egfr Igf1r and Sphingosine Kinase Signalingmentioning

confidence: 99%

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

Baxter

2013

J. Cell Commun. Signal.

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In addition to its important role in the regulation of somatic growth by acting as the major circulating transport protein for the insulin-like growth factors (IGFs), IGF binding protein-3 (IGFBP-3) has a variety of intracellular ligands that point to its function within major signaling pathways. The discovery of its interaction with the retinoid X receptor has led to the elucidation of roles in regulating the function of several nuclear hormone receptors including retinoic acid receptor-α, Nur77 and vitamin D receptor. Its interaction with the nuclear hormone receptor peroxisome proliferator-activated receptor-γ is believed to be involved in regulating adipocyte differentiation, which is also modulated by IGFBP-3 through an interaction with TGFβ/Smad signaling. IGFBP-3 can induce apoptosis alone or in conjunction with other agents, and in different systems can activate caspases −8 and −9. At least two unrelated proteins (LRP1 and TMEM219) have been designated as receptors for IGFBP-3, the latter with a demonstrated role in inducing caspase-8-dependent apoptosis. In contrast, IGFBP-3 also has demonstrated roles in survival-related functions, including the repair of DNA double-strand breaks through interaction with the epidermal growth factor receptor and DNAdependent protein kinase, and the induction of autophagy through interaction with GRP78. The ability of IGFBP-3 to modulate the balance between pro-apoptotic and prosurvival sphingolipids by regulating sphingosine kinase 1 and sphingomyelinases may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli. The pleiotropic nature of IGFBP-3 activity supports the idea that IGFBP-3 itself, or pathways with which it interacts, should be investigated as targets of therapy for a variety of diseases.

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“…These subunits are key components of NHEJ in the DNA repair pathway; hence, they increase the activity of the DNA-PK-dependent non-homologous endjoining (D-NHEJ) system (Szumiel, 2006). The overall DSB repair capacity is clearly enhanced when EGFR is activated by its natural ligand, which is the epidermal growth factor (EGF); on the other hand, it was reduced when EGFR was blocked either by the specific antibody cetuximab or the tyrosine kinase inhibitor erlotinib (Kriegs et al, 2010). Recent radiosensitivity effects in clinical practice have shown that EGFR inhibitors counteract the nuclear translocation of DNA-PK subunits.…”

Section: Dna Damage Repairmentioning

confidence: 99%

Epidermal Growth Factor Receptor-Related DNA Repair and Radiation-Resistance Regulatory Mechanisms: A Mini-Review

Bai

Guo²,

Bai³

2012

Asian Pacific Journal of Cancer Prevention

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The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining

Cited by 108 publications

References 40 publications

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

Epidermal Growth Factor Receptor-Related DNA Repair and Radiation-Resistance Regulatory Mechanisms: A Mini-Review

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