ADAM17 regulates epidermal growth factor receptor expression through the activation of Notch1 in non-small cell lung cancer
| Autor: | Anja Baumgart, Falko Fend, Ina Koch, Nadya Mitova, Tobias Dechow, Justus Duyster, Lars Michel, Marcus Kremer, Petros Vlachou, Jens T. Siveke, Nicole Schatz, Tibor Schuster, Christian Peschel, Rebekka Grundler, Katja Specht, Stefan Seidl |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
medicine.medical_specialty Cell cycle checkpoint Lung Neoplasms Cell Survival Cell Transplantation Heterologous Cell Growth Processes ADAM17 Protein medicine.disease_cause Mice Growth factor receptor Internal medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Basic Helix-Loop-Helix Transcription Factors Animals Humans Epidermal growth factor receptor Receptor Notch1 Homeodomain Proteins Gene knockdown biology Epidermal Growth Factor ErbB Receptors ADAM Proteins Endocrinology medicine.anatomical_structure Cell Transformation Neoplastic Oncology embryonic structures Cancer research biology.protein Transcription Factor HES-1 Ectopic expression Signal transduction Carcinogenesis Signal Transduction |
| Zdroj: | Cancer research. 70(13) |
| ISSN: | 1538-7445 |
| Popis: | Epidermal growth factor receptor (EGFR) overexpression and activation are hallmarks of non–small cell lung carcinoma (NSCLC). Although EGFR-targeted therapies are used, the prognosis of NSCLC remains poor. ADAM17 induces activation of the EGFR through ligand cleavage. However, we show that inhibition or knockdown of ADAM17 markedly reduces tumorigenesis and survival to a large part independently from EGFR ligand shedding in NSCLC cells. These findings strongly indicate additional oncogenic mechanisms regulated by ADAM17. We identified Notch1 signaling as an ADAM17-controlled pathway and a critical regulator of anchorage-independent growth by using both Notch1 shRNA and ectopic expression of the active intracellular Notch1 fragment. Strikingly, Notch1 knockdown led to a strong reduction of EGFR expression in all analyzed cell lines. Proliferation, survival, and colony formation of Notch1-deficient cells were insensitive to EGF stimulation. Moreover, targeting Notch1 or ADAM17 resulted in substantial cell death, whereas EGFR inhibition predominantly induced cell cycle arrest. Immunohistochemical analysis of primary human tissue revealed a significant correlation between ADAM17, Notch1 signaling, and high EGFR expression levels. In conclusion, this article describes a novel molecular circuitry in NSCLC, incorporating ADAM17 as a regulator of EGFR expression through the activation of Notch1. Due to their central role in tumorigenesis and survival of NSCLC cells, both ADAM17 and Notch1 constitute promising targets for the treatment of NSCLC. Cancer Res; 70(13); 5368–78. ©2010 AACR. |
| Databáze: | OpenAIRE |
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