Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma.

Autor:	Walsh AM; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania., Kapoor GS; Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania., Buonato JM; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania., Mathew LK; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Howared Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania., Bi Y; Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania., Davuluri RV; Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania., Martinez-Lage M; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Simon MC; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Howared Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania., O'Rourke DM; Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Lazzara MJ; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania. mlazzara@seas.upenn.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2015 Aug; Vol. 13 (8), pp. 1227-37. Date of Electronic Publication: 2015 May 01.
DOI:	10.1158/1541-7786.MCR-14-0183-T
Abstrakt:	Unlabelled: Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of data from clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM. Implications: SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs, thus making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma. (©2015 American Association for Cancer Research.)
Databáze:	MEDLINE
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