PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells Journal Article


Authors: Bleau, A. M.; Hambardzumyan, D.; Ozawa, T.; Fomchenko, E. I.; Huse, J. T.; Brennan, C. W.; Holland, E. C.
Article Title: PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells
Abstract: In normal brain, the side population (SP) phenotype is generated by ABC transporter activity and identifies stem cell and endothelial cell subpopulations by dye exclusion. By drug efflux, the ABCG2 transporter provides chemoresistance in stem cells and contributes to the blood brain barrier (BBB) when active in endothelial cells. We investigated the SP phenotype of mouse and human gliomas. In glioma endothelial cells, ABC transporter function is impaired, corresponding to disruption of the BBB in these tumors. By contrast, the SP phenotype is increased in nonendothelial cells that form neurospheres and are highly tumorigenic. In this cell population, Akt, but not its downstream target mTOR, regulates ABCG2 activity, and loss of PTEN increases the SP. This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN. © 2009 Elsevier Inc. All rights reserved.
Keywords: protein kinase b; controlled study; human cell; nonhuman; antineoplastic agents; temozolomide; glioma; protein function; animal cell; mouse; phenotype; animals; mice; animal tissue; atp-binding cassette transporters; cells, cultured; dacarbazine; neoplasm proteins; animal experiment; animal model; antineoplastic activity; drug resistance, neoplasm; phosphatidylinositol 3 kinase; cancer resistance; endothelium cell; mice, nude; brain; neoplastic stem cells; enzyme inhibitors; mammalian target of rapamycin; stemcell; breast cancer resistance protein; mitoxantrone; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; blood brain barrier; cancer stem cell; carcinogenicity; cell membrane; cell subpopulation; newborn; protein transport; 1-phosphatidylinositol 3-kinase; antineoplastic agents, alkylating; blood-brain barrier; chromones; morpholines; platelet-derived growth factor; proto-oncogene proteins c-akt; pten phosphohydrolase
Journal Title: Cell Stem Cell
Volume: 4
Issue: 3
ISSN: 1934-5909
Publisher: Cell Press  
Date Published: 2009-03-06
Start Page: 226
End Page: 235
Language: English
DOI: 10.1016/j.stem.2009.01.007
PUBMED: 19265662
PROVIDER: scopus
PMCID: PMC3688060
DOI/URL:
Notes: --- - "Cited By (since 1996): 66" - "Export Date: 30 November 2010" - "Source: Scopus"
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MSK Authors
  1. Cameron Brennan
    192 Brennan
  2. Anne-Marie Bleau
    11 Bleau
  3. Eric Holland
    224 Holland
  4. Jason T Huse
    133 Huse
  5. Tatsuya Ozawa
    16 Ozawa