PittsburghV1, Main, Exploration, bibRecord, 001410

Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Identifieur interne : 001410 ( Main/Exploration ); précédent : 001409; suivant : 001411

Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Auteurs : N. Panupinthu [Thaïlande] ; S. Yu [États-Unis] ; D. Zhang [États-Unis] ; F. Zhang [États-Unis] ; M. Gagea [États-Unis] ; Y. Lu [États-Unis] ; J R Grandis [États-Unis] ; S E Dunn [Canada] ; H Y Lee [Corée du Sud] ; G B Mills [États-Unis]

Source :

Oncogene [ 1476-5594 ] ; 2014.

RBID : pubmed:23851501

Descripteurs français

English descriptors

KwdEn :
- Amphiregulin, Animals, Cell Line, Tumor, Disease Models, Animal, EGF Family of Proteins, Female, Glycoproteins (metabolism), Humans, Intercellular Signaling Peptides and Proteins (metabolism), Mice, Mitogen-Activated Protein Kinase 3 (metabolism), Ovarian Neoplasms (metabolism), Ovarian Neoplasms (mortality), Ovarian Neoplasms (pathology), Phosphorylation, Prognosis, Protein Binding, Proto-Oncogene Proteins pp60(c-src) (metabolism), Receptor, Epidermal Growth Factor (metabolism), Ribosomal Protein S6 Kinases, 90-kDa (metabolism), Signal Transduction, Xenograft Model Antitumor Assays, Y-Box-Binding Protein 1 (metabolism).
MESH :
- chemical , metabolism : Glycoproteins, Intercellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 3, Proto-Oncogene Proteins pp60(c-src), Receptor, Epidermal Growth Factor, Ribosomal Protein S6 Kinases, 90-kDa, Y-Box-Binding Protein 1.
- chemical : Amphiregulin, EGF Family of Proteins.
- metabolism : Ovarian Neoplasms.
- mortality : Ovarian Neoplasms.
- pathology : Ovarian Neoplasms.
- Animals, Cell Line, Tumor, Disease Models, Animal, Female, Humans, Mice, Phosphorylation, Prognosis, Protein Binding, Signal Transduction, Xenograft Model Antitumor Assays.

Abstract

The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.

DOI: 10.1038/onc.2013.259
PubMed: 23851501

Affiliations:

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amphiregulin</term>
<term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Disease Models, Animal</term>
<term>EGF Family of Proteins</term>
<term>Female</term>
<term>Glycoproteins (metabolism)</term>
<term>Humans</term>
<term>Intercellular Signaling Peptides and Proteins (metabolism)</term>
<term>Mice</term>
<term>Mitogen-Activated Protein Kinase 3 (metabolism)</term>
<term>Ovarian Neoplasms (metabolism)</term>
<term>Ovarian Neoplasms (mortality)</term>
<term>Ovarian Neoplasms (pathology)</term>
<term>Phosphorylation</term>
<term>Prognosis</term>
<term>Protein Binding</term>
<term>Proto-Oncogene Proteins pp60(c-src) (metabolism)</term>
<term>Receptor, Epidermal Growth Factor (metabolism)</term>
<term>Ribosomal Protein S6 Kinases, 90-kDa (metabolism)</term>
<term>Signal Transduction</term>
<term>Xenograft Model Antitumor Assays</term>
<term>Y-Box-Binding Protein 1 (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Amphiréguline</term>
<term>Animaux</term>
<term>Femelle</term>
<term>Glycoprotéines (métabolisme)</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire tumorale</term>
<term>Mitogen-Activated Protein Kinase 3 (métabolisme)</term>
<term>Modèles animaux de maladie humaine</term>
<term>Phosphorylation</term>
<term>Pronostic</term>
<term>Protéine-1 de liaison à la boîte Y (métabolisme)</term>
<term>Protéines de la famille de l'EGF</term>
<term>Protéines et peptides de signalisation intercellulaire (métabolisme)</term>
<term>Protéines proto-oncogènes pp60(c-src) (métabolisme)</term>
<term>Ribosomal Protein S6 Kinases, 90-kDa (métabolisme)</term>
<term>Récepteur du facteur de croissance épidermique (métabolisme)</term>
<term>Souris</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
<term>Transduction du signal</term>
<term>Tumeurs de l'ovaire (anatomopathologie)</term>
<term>Tumeurs de l'ovaire (mortalité)</term>
<term>Tumeurs de l'ovaire (métabolisme)</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glycoproteins</term>
<term>Intercellular Signaling Peptides and Proteins</term>
<term>Mitogen-Activated Protein Kinase 3</term>
<term>Proto-Oncogene Proteins pp60(c-src)</term>
<term>Receptor, Epidermal Growth Factor</term>
<term>Ribosomal Protein S6 Kinases, 90-kDa</term>
<term>Y-Box-Binding Protein 1</term>
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<term>EGF Family of Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs de l'ovaire</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Ovarian Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="mortality" xml:lang="en"><term>Ovarian Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="mortalité" xml:lang="fr"><term>Tumeurs de l'ovaire</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéines</term>
<term>Mitogen-Activated Protein Kinase 3</term>
<term>Protéine-1 de liaison à la boîte Y</term>
<term>Protéines et peptides de signalisation intercellulaire</term>
<term>Protéines proto-oncogènes pp60(c-src)</term>
<term>Ribosomal Protein S6 Kinases, 90-kDa</term>
<term>Récepteur du facteur de croissance épidermique</term>
<term>Tumeurs de l'ovaire</term>
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<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Ovarian Neoplasms</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Humans</term>
<term>Mice</term>
<term>Phosphorylation</term>
<term>Prognosis</term>
<term>Protein Binding</term>
<term>Signal Transduction</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Amphiréguline</term>
<term>Animaux</term>
<term>Femelle</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire tumorale</term>
<term>Modèles animaux de maladie humaine</term>
<term>Phosphorylation</term>
<term>Pronostic</term>
<term>Protéines de la famille de l'EGF</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.</div>
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   |clé=     pubmed:23851501
   |texte=   Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.
}}

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Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

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