Nuclear EGFR Suppresses Ribonuclease Activity of Polynucleotide Phosphorylase through DNAPK-mediated Phosphorylation at Serine 776

Yu, Yung Luen; Chou, Ruey Hwang; Wu, Chia Han; Wang, Ying-Nai; Chang, Wei; Tseng, Yen Ju; Chang, Wei Chao; Lai, Chien‐Chen; Lee, Hong Jen; Huo, Longfei; Chen, Chung Hsuan; Hung, Mien Chie

doi:10.1074/jbc.m112.358077

Cited by 42 publications

(34 citation statements)

References 46 publications

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“…Cellular Fractionation. The cytosolic and nuclear fractions were extracted as previously described (51). Briefly, cells were washed twice with ice-cold PBS, harvested by scraping with a rubber policeman, and lysed in buffer A (20 mM Hepes, pH 7.0, 10 mM KCl, 2 mM MgCl 2 , 0.5% Nonidet P-40, 1 mM Na 3 VO 4 , 10 mM NaF) containing protease inhibitor mixture (Roche).…”

Section: Methodsmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

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Section: Methodsmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, inhibition of EGFR with cetuximab attenuates EGFR nuclear import and suppresses DNA-PK activity (Dittmann et al, 2005). EGFR also affects the DNA repair proteins XRCC1 and ATM (Debucquoy et al, 2010) and interacts with the ribonuclease PNPase through DNA-PK mediated phosphorylation leading to increased radioresistance (Yu et al, 2012). Finally, nuclear EGFR phosphorylates PCNA which plays an important role in recruiting DNA polymerase, DNA ligase, and other DNA repair proteins (Wang et al, 2006, Stoimenov et al, 2009).…”

Section: Interaction Of Egfr With Radiation and Chemotherapymentioning

confidence: 99%

EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection

Cuneo

Nyati

Ray

et al. 2015

Pharmacology & Therapeutics

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The epidermal growth factor receptor (EGFR) plays an important role in tumor progression and treatment resistance for many types of malignancies including head and neck, colorectal, and nonsmall cell lung cancer. Several EGFR targeted therapies are efficacious as single agents or in combination with chemotherapy. Given the toxicity associated with chemoradiation and poor outcomes seen in several types of cancers, combinations of EGFR targeted agents with or without chemotherapy have been tested in patients receiving radiation. To date, the only FDA approved use of an anti-EGFR therapy in combination with radiation therapy is for locally advanced head and neck cancer. Given the important role EGFR plays in lung and colorectal cancer and the benefit of EGFR inhibition combined with chemotherapy in these disease sites, it is perplexing why EGFR targeted therapies in combination with radiation or chemoradiation have not been more successful. In this review we summarize the clinical findings of EGFR targeted therapies combined with radiation and chemoradiation regimens. We then discuss the interaction between EGFR and radiation including radiation induced EGFR signaling, the effect of EGFR on DNA damage repair, and potential mechanisms of radiosensitization. Finally, we examine the potential pitfalls with scheduling EGFR targeted therapies with chemoradiation and the use of predictive biomarkers to improve patient selection.

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“…This association enhances kinase activity of the DNAPK complex increasing the repair of DNA strand breaks (SB; refs. 11,13,14). In addition, EGFR can also directly activate the proliferation cell nuclear antigen, essential for the DNA sliding clamp involved in DNA replication and DNA repair (15).…”

Section: Introductionmentioning

confidence: 99%

Importance of EGFR/ERCC1 Interaction Following Radiation-Induced DNA Damage

Liccardi

Hartley

Hochhauser

2014

Clinical Cancer Research

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Purpose: The epidermal growth factor receptor (EGFR) plays an important role in cellular response to chemotherapy and radiotherapy through modulation of DNA repair. EGFR activates DNA-dependent protein kinase (DNA-PK) stimulating repair of DNA strand breaks (SB) and interstrand crosslinks (ICL). We investigated the role of EGFR in repair of ionizing radiation (IR)-induced SB independently of DNA-PK.Experimental Design: The EGFR interactome was investigated via mass spectrometry. IR-induced EGFR-ERCC1 binding was validated biochemically and via proximity ligation assay in different cell lines including the M059K and M059J glioma cell lines, proficient and deficient for the expression of DNAPKcs, respectively. EGFR-ERCC1 functional significance following IR-induced SB was investigated in knockdown experiments with the Comet and gH2AX foci assays. The effect of this interaction was tested with EGFR-ERCC1 knockdown in combination with gefitinib and NU7026 using the MTT and apoptosis assays.Results: This study demonstrates that EGFR inhibition further impairs IR-induced DNA repair in cells lacking expression of DNAPKcs or in combination with the DNAPK inhibitor NU7026. Our data suggest a role for EGFR in DNA repair independent of DNAPKcs but dependent on ERCC1. Alkaline comet and gH2AX foci assays in cells depleted of EGFR, ERCC1, or EGFR-ERCC1 expression demonstrated involvement of this interaction in DNA repair. Cellular survival and apoptosis data correlate with levels of residual DNA damage underlying the importance of this complex following SB.Conclusion: These data emphasize the importance of understanding the various mechanisms by which EGFR modulates DNA repair to optimize targeted therapy for patients with cancer.

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Nuclear EGFR Suppresses Ribonuclease Activity of Polynucleotide Phosphorylase through DNAPK-mediated Phosphorylation at Serine 776

Cited by 42 publications

References 46 publications

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection

Importance of EGFR/ERCC1 Interaction Following Radiation-Induced DNA Damage

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