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

N. Panupinthu, S. Yu, D. Zhang, F. Zhang, M. Gagea, Y. Lu, J. R. Grandis, S. E. Dunn, H. Y. Lee, G. B. Mills

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2846-2856
Number of pages11
JournalOncogene
Volume33
Issue number22
DOIs
StatePublished - May 29 2014

Keywords

  • G-protein-coupled receptor
  • autoregulation
  • crosstalk
  • feedback
  • receptor tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Panupinthu, N., Yu, S., Zhang, D., Zhang, F., Gagea, M., Lu, Y., Grandis, J. R., Dunn, S. E., Lee, H. Y., & Mills, G. B. (2014). Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. Oncogene, 33(22), 2846-2856. https://doi.org/10.1038/onc.2013.259