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Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer
- Source :
- Oncogene. 33:2846-2856
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
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.
- Subjects :
- MAPK/ERK pathway
EGF Family of Proteins
Cancer Research
Proto-Oncogene Proteins pp60(c-src)
Biology
Amphiregulin
Ribosomal Protein S6 Kinases, 90-kDa
Article
Mice
Transactivation
Cell Line, Tumor
Genetics
Animals
Humans
Epidermal growth factor receptor
Phosphorylation
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Glycoproteins
Ovarian Neoplasms
Mitogen-Activated Protein Kinase 3
Prognosis
Xenograft Model Antitumor Assays
ErbB Receptors
Disease Models, Animal
Cancer research
biology.protein
Intercellular Signaling Peptides and Proteins
Female
Y-Box-Binding Protein 1
Signal transduction
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....2d9c022fc78d5576c223fc4a3b74edd2