title: ADAM17 regulates epidermal growth factor receptor expression through the activation of Notch1 in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Department of Internal Medicine III, Technische Universitat Munchen, Ismaninger Strasse 22, Munich, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Baumgart
authors.forename: Stefan
authors.initials: S
authors.lastname: Seidl
authors.forename: Petros
authors.initials: P
authors.lastname: Vlachou
authors.forename: Lars
authors.initials: L
authors.lastname: Michel
authors.forename: Nadya
authors.initials: N
authors.lastname: Mitova
authors.forename: Nicole
authors.initials: N
authors.lastname: Schatz
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.forename: Ina
authors.initials: I
authors.lastname: Koch
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Rebekka
authors.initials: R
authors.lastname: Grundler
authors.forename: Marcus
authors.initials: M
authors.lastname: Kremer
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Tobias
authors.initials: T
authors.lastname: Dechow
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014183:Transplantation, Heterologous
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C497761:NOTCH1 protein, human; C078493:HES1 protein, human; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse