Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

Autor: Laetitia Vanwonterghem, Jean-Luc Coll, Beatrice Eymin, Marie Guerard, Laurence David-Boudet, Sylvie Gazzeri, P. Perron, Anne-Sophie Hatat, Amandine Hurbin, Thomas Robin, Benoit Busser, Sylvie Lantuejoul
Přispěvatelé: Team 'RNA splicing, cell signaling and response to therapies', Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Team 'Cancer targets and experimental therapeutics', Centre Hospitalier Universitaire [Grenoble] (CHU), Eymin, Beatrice, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Lung Neoplasms
[SDV]Life Sciences [q-bio]
Apoptosis
MESH: EGFR-TKI
IGF1R
Lung cancer
Nuclear trafficking
Resistance
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Amphiregulin
Receptor tyrosine kinase
Receptor
IGF Type 1
03 medical and health sciences
Gefitinib
Epidermal growth factor
Cell Line
Tumor
medicine
Humans
skin and connective tissue diseases
Protein Kinase Inhibitors
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Insulin-like growth factor 1 receptor
Cell Nucleus
biology
Chemistry
Receptors
Somatomedin
Cell Cycle Checkpoints
medicine.disease
Adenocarcinoma
Mucinous
Xenograft Model Antitumor Assays
respiratory tract diseases
3. Good health
[SDV] Life Sciences [q-bio]
body regions
Protein Transport
Cell nucleus
030104 developmental biology
medicine.anatomical_structure
Oncology
A549 Cells
Drug Resistance
Neoplasm
Cancer research
biology.protein
Signal transduction
Signal Transduction
medicine.drug
Zdroj: Cancer Letters
Cancer Letters, 2018, 420, pp.146-155. ⟨10.1016/j.canlet.2018.01.080⟩
Cancer Letters, Elsevier, 2018, 420, pp.146-155. ⟨10.1016/j.canlet.2018.01.080⟩
ISSN: 0304-3835
Popis: International audience; Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xeno-grafts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-b1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer.
Databáze: OpenAIRE
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