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.
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Abbreviations
- AREG:
-
Amphiregulin
- EGFR:
-
Epidermal growth factor receptor
- GPCR:
-
G-protein-coupled receptor
- HER:
-
human epidermal growth factor receptor
- IGF-1:
-
insulin-like growth factor 1
- IGF1R:
-
insulin-like growth factor 1 receptor
- LPA:
-
lysophosphatidic acid
- LPAR:
-
lysophosphatidic acid receptor
- p90RSK:
-
p90 ribosomal S6 kinase
- PI3K:
-
phosphatidylinositol 3-kinase
- RPPA:
-
reverse phase protein array
- TCGA:
-
The Cancer Genome Atlas
- TGFα:
-
transforming growth factor-α
- YB-1:
-
Y-box binding protein-1
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Acknowledgements
We thank Drs Meng Gao and Zhiyong Ding at MD Anderson Cancer Center for authenticating the AKT1/AKT2 knockout cell lines. This work was supported by NIH grants R01CA92160 and P01CA099031 (to G.B.M.), and R01CA098372 (to J.R.G.), the Breast Cancer Research Foundation (to G.B.M.), the National Research Foundation of Korea 2011-0015761 (to H.Y.L.), Canadian Institutes of Health Research (to S.E.D.), the SPORE in head-and-neck cancer P50CA197190 (to J.R.G.), the American Cancer Society (to J.R.G.) and CCSG core grant CA16672 (to MD Anderson Cancer Center).
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Panupinthu, N., Yu, S., Zhang, D. et al. Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene 33, 2846–2856 (2014). https://doi.org/10.1038/onc.2013.259
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DOI: https://doi.org/10.1038/onc.2013.259
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