The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

Autor: Christel Larbouret, Marie Alix Poul, Thierry Chardès, André Pèlegrin, Gerry Melino, Philippe Mondon, Christophe Le Clorennec, Yassamine Lazrek, Olivier Dubreuil
Přispěvatelé: Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), Millegen SA, MILEGEN-Immeuble BIOSTEP, GamaMabs Pharma SA [Toulouse] ( Centre Pierre Potier), Oncopole de Toulouse-Centre Pierre Potier [Toulouse], LFB Biotechnologies [Lille, France], Università degli Studi di Roma Tor Vergata [Roma], University of Leicester, Herrada, Anthony
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cell cycle checkpoint
Receptor
ErbB-3
MESH: Down-Regulation
MESH: Antibodies
Monoclonal
Antibodies
Monoclonal
Murine-Derived
0302 clinical medicine
Ubiquitin
antibody
Medicine
skin and connective tissue diseases
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
treatment
Antibodies
Monoclonal
3. Good health
Ubiquitin ligase
ITCH/AIP4
MESH: Receptor
ErbB-3
Oncology
MESH: Repressor Proteins
030220 oncology & carcinogenesis
MESH: Mitogen-Activated Protein Kinase 9
Phosphorylation
MESH: Mitogen-Activated Protein Kinase 8
Research Paper
MESH: Cell Line
Tumor
MAP Kinase Signaling System
Ubiquitin-Protein Ligases
Down-Regulation
[SDV.CAN]Life Sciences [q-bio]/Cancer
Antineoplastic Agents
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
HER3
Cell Line
Tumor
cancer
Humans
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinase 8
Settore BIO/10
Protein kinase B
PI3K/AKT/mTOR pathway
MESH: Humans
business.industry
MESH: MAP Kinase Signaling System
Ubiquitination
MESH: Ubiquitin-Protein Ligases
body regions
Repressor Proteins
030104 developmental biology
USP9X
MESH: Antibodies
Monoclonal
Murine-Derived
Cancer cell
Immunology
biology.protein
Cancer research
MESH: Ubiquitination
MESH: Antineoplastic Agents
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Oncotarget
Oncotarget, Impact journals, 2016, 7 (24), pp.37013-37029. ⟨10.18632/oncotarget.9455⟩
ISSN: 1949-2553
DOI: 10.18632/oncotarget.9455⟩
Popis: International audience; We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.
Databáze: OpenAIRE
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