EGF Receptor Inhibition Radiosensitizes NSCLC Cells by Inducing Senescence in Cells Sustaining DNA Double-Strand Breaks

Wang, Meng; Morsbach, Fabian; Sander, David M.; Gheorghiu, Liliana; Nanda, Akash; Benes, Cyril H.; Kriegs, Malte; Krause, Mechthild; Dikomey, Ekkehard; Baumann, Michaël; Dahm-Daphi, Jochen; Settleman, Jeffrey; Willers, Henning

doi:10.1158/0008-5472.can-11-0213

Cited by 98 publications

(115 citation statements)

References 49 publications

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“…Thus, our results indicated that the downregulation of EGFR alone might be sufficient for the induction of senescence in some GBM cells. Our findings are in contrast with the report that inhibition of EGFR could radiosensitize non-small cell lung cancer cells by inducing senescence in cells sustaining DSBs (30). Berberine inhibits the EGFR-MEK-ERK signaling pathway.…”

Section: Discussioncontrasting

confidence: 99%

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Zhao

et al. 2015

Molecular Cancer Therapeutics

103

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Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and has a poor prognosis. We, here, report a potent antitumor effect of berberine, an isoquinoline alkaloid, on GBM. Berberine was found to have an IC 50 that is much lower than temozolomide in vitro in U87, U251, and U118 glioblastoma cells. Although previous studies showed that berberine primarily exerts its anticancer effect by inducing cell-cycle arrest, apoptosis, and autophagy, we observed that the antitumor effect of berberine on glioblastoma cells was primarily achieved through induction of cellular senescence. In glioblastoma cells treated with berberine, the level of epidermal growth factor receptor (EGFR) was greatly reduced. Examination of the activities of the kinases downstream of EGFR revealed that the RAF-MEK-ERK signaling pathway was remarkably inhibited, whereas AKT phosphorylation was not altered. Pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Furthermore, the cellular senescence induced by berberine could be rescued by introduction of a constitutive active MKK. Berberine also potently inhibited the growth of tumor xenografts, which was accompanied by downregulation of EGFR and induction of senescence. Our findings thus revealed a new route by which berberine exerts its anticancer activity. Because EGFR is commonly upregulated in glioblastoma, the demonstration of effective inhibition of EGFR by berberine points to the possibility of using berberine in the treatment of patients with glioblastoma.

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Section: Discussioncontrasting

confidence: 99%

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Zhao

et al. 2015

Molecular Cancer Therapeutics

103

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“…HB-EGF was found to protect cells from chemotherapy-induced cell death. (31) Moreover, EGFR inhibition was shown to induce cellular senescence in response to radiation and this was attributed to an increase in the levels of nonrepairable DSBs (32), suggesting a link between the EGF:EGFR pathway and the process of DNA damage repair. Finally, a previous study has demonstrated that in tumor cells exposed to ionizing radiation, activation of EGFR by EGF enhances the DSB repair capacity, whereas inhibition of EGFR attenuates DSB rejoining (33)(34)(35).…”

Section: Monocytes Enhance Ddr Via Hb-egf Releasementioning

confidence: 99%

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

et al. 2015

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The DNA damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity. Cancer Res; 75(13); 2663-73. Ó2015 AACR.

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“…Possibly operating similarly, the EGFR-blocking antibody cetuximab reportedly sensitizes lung cancer cells to irradiation-induced senescence (while not producing senescence on its own; ref. 43), and recently, increased SA-b-gal activity became detectable after application of obinutuzumab, another CD20-directed antibody, in a cell line-based model of follicular lymphoma (44). Importantly, RTX-induced senescence does not seem to primarily damage DNA, as other non-genotoxic stimuli have been shown to produce cellular senescence (16,20,45).…”

Section: E Dmentioning

confidence: 99%

CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma

Däbritz

Milanovic³

et al. 2016

Molecular Cancer Therapeutics

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The CD20-targeting monoclonal antibody rituximab is an established component of immunochemotherapeutic regimens against B-cell lymphomas, where its coadministration with conventional anticancer agents has significantly improved long-term outcome. However, the cellular mechanisms by which rituximab exerts its antilymphoma activity are only partially understood. We show here that rituximab induces typical features of cellular senescence, a long-term growth arrest of viable cells with distinct biologic properties, in established B-cell lymphoma cell lines as well as primary transformed B cells. In addition, rituximab-based immunotherapy sensitized lymphoma cells to senescence induction by the chemotherapeutic compound adriamycin (a.k.a. doxorubicin), and, to a lesser extent, by the antimicrotubule agent vincristine. Anti-CD20 treatment further enhanced secretion of senescence-associated cytokines, and augmented the DNA damage response signaling cascade triggered by adriamycin. As the underlying prosenescence mechanism, we found intracellular reactive oxygen species (ROS) levels to be elevated in response to rituximab, and, in turn, the ROS scavenger Nacetylcysteine to largely abrogate rituximab-mediated senescence. Our results, further supported by gene set enrichment analyses in a clinical data set of chronic lymphocytic leukemia patient samples exposed to a rituximab-containing treatment regimen, provide important mechanistic insights into the biologic complexity of anti-CD20-evoked tumor responses, and unveil cellular senescence as a hitherto unrecognized effector principle of the antibody component in lymphoma immunochemotherapy. Mol Cancer Ther; 15(5); 1074-81. Ó2016 AACR.

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EGF Receptor Inhibition Radiosensitizes NSCLC Cells by Inducing Senescence in Cells Sustaining DNA Double-Strand Breaks

Cited by 98 publications

References 49 publications

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma

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