PMID- 23851501 OWN - NLM STAT- MEDLINE DCOM- 20140722 LR - 20211021 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 33 IP - 22 DP - 2014 May 29 TI - Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. PG - 2846-56 LID - 10.1038/onc.2013.259 [doi] AB - 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. FAU - Panupinthu, N AU - Panupinthu N AD - 1] Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand. FAU - Yu, S AU - Yu S AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Zhang, D AU - Zhang D AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Zhang, F AU - Zhang F AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Gagea, M AU - Gagea M AD - Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Lu, Y AU - Lu Y AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Grandis, J R AU - Grandis JR AD - Department of Otolaryngology and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Dunn, S E AU - Dunn SE AD - Departments of Pediatrics and Experimental Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. FAU - Lee, H Y AU - Lee HY AD - Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Republic of Korea. FAU - Mills, G B AU - Mills GB AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P50CA197190/CA/NCI NIH HHS/United States GR - CA16672/CA/NCI NIH HHS/United States GR - CAPMC/CIHR/Canada GR - P01CA099031/CA/NCI NIH HHS/United States GR - P50 CA098258/CA/NCI NIH HHS/United States GR - R01CA098372/CA/NCI NIH HHS/United States GR - R01 CA098372/CA/NCI NIH HHS/United States GR - P50 CA083639/CA/NCI NIH HHS/United States GR - P01 CA099031/CA/NCI NIH HHS/United States GR - R01 DE023685/DE/NIDCR NIH HHS/United States GR - R01CA92160/CA/NCI NIH HHS/United States GR - R01 CA092160/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130715 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (EGF Family of Proteins) RN - 0 (Glycoproteins) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Y-Box-Binding Protein 1) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src)) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) SB - IM MH - Amphiregulin MH - Animals MH - Cell Line, Tumor MH - Disease Models, Animal MH - EGF Family of Proteins MH - ErbB Receptors/metabolism MH - Female MH - Glycoproteins/*metabolism MH - Humans MH - Intercellular Signaling Peptides and Proteins/*metabolism MH - Mice MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Ovarian Neoplasms/*metabolism/*mortality/pathology MH - Phosphorylation MH - Prognosis MH - Protein Binding MH - Proto-Oncogene Proteins pp60(c-src)/metabolism MH - Ribosomal Protein S6 Kinases, 90-kDa/metabolism MH - Signal Transduction MH - Xenograft Model Antitumor Assays MH - Y-Box-Binding Protein 1/*metabolism PMC - PMC4115609 MID - NIHMS607350 EDAT- 2013/07/16 06:00 MHDA- 2014/07/23 06:00 PMCR- 2014/07/30 CRDT- 2013/07/16 06:00 PHST- 2013/02/14 00:00 [received] PHST- 2013/05/05 00:00 [revised] PHST- 2013/05/06 00:00 [accepted] PHST- 2013/07/16 06:00 [entrez] PHST- 2013/07/16 06:00 [pubmed] PHST- 2014/07/23 06:00 [medline] PHST- 2014/07/30 00:00 [pmc-release] AID - onc2013259 [pii] AID - 10.1038/onc.2013.259 [doi] PST - ppublish SO - Oncogene. 2014 May 29;33(22):2846-56. doi: 10.1038/onc.2013.259. Epub 2013 Jul 15.