mTOR promotes survival and astrocytic characteristics induced by Pten/Akt signaling in glioblastoma Journal Article

Authors: Hu, X.; Pandolfi, P. P.; Li, Y.; Koutcher, J. A.; Rosenblum, M.; Holland, E. C.
Article Title: mTOR promotes survival and astrocytic characteristics induced by Pten/Akt signaling in glioblastoma
Abstract: Combined activation of Ras and Akt leads to the formation of astrocytic glioblastoma multiforme (GBM) in mice. In human GBMs, AKT is not mutated but is activated in approximately 70% of these tumors, in association with loss of PTEN and/or activation of receptor tyrosine kinases. Mechanistic justification for the therapeutic blockade of targets downstream of AKT, such as mTOR, in these cancers requires demonstration that the oncogenic effect of PTEN loss is through elevated AKT activity. We demonstrate here that loss of Pten is similar to Akt activation in the context of glioma formation in mice. We further delineate the role of mTOR activity downstream of Akt in the maintenance of Akt+KRas-induced GBMs. Blockade of mTOR results in regional apoptosis in these tumors and conversion in the character of surviving tumor cells from astrocytoma to oligodendroglioma. These data suggest that mTOR activity is required for the survival of some cells within these GBMs, and mTOR appears required for the maintenance of astrocytic character in the surviving cells. Furthermore, our study provides the first example of conversion between two distinct tumor types usually thought of as belonging to specific lineages, and provides evidence for signal transduction-mediated transdifferentiation between glioma subtypes. Copyright © 2005 Neoplasia Press, Inc. All rights reserved.
Keywords: immunohistochemistry; signal transduction; survival; mitogen activated protein kinase; protein kinase b; controlled study; mutation; exons; proto-oncogene proteins; nonhuman; glioma; brain neoplasms; polymerase chain reaction; animal cell; mouse; animals; mice; animal tissue; cell survival; cells, cultured; apoptosis; map kinase signaling system; protein kinases; protein depletion; animal experiment; animal model; cell differentiation; neurons; enzyme activation; enzyme activity; cell line, tumor; mice, inbred c57bl; cell lineage; mice, transgenic; temsirolimus; blotting, western; brain; protein-serine-threonine kinases; glioblastoma; mammalian target of rapamycin; tumor suppressor proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; tumor cell; stem cells; green fluorescent proteins; plasmids; models, genetic; oligodendroglioma; cancer classification; akt; pten; k ras protein; nerve cell; astrocytoma; phosphoric monoester hydrolases; rapamycin; sirolimus; mtor; 2 morpholino 8 phenylchromone; in situ nick-end labeling
Journal Title: NeoPlasia
Volume: 7
Issue: 4
ISSN: 1522-8002
Publisher: Elsevier Science Inc.  
Date Published: 2005-04-01
Start Page: 356
End Page: 368
Language: English
DOI: 10.1593/neo.04595
PUBMED: 15967113
PROVIDER: scopus
PMCID: PMC1501155
Notes: --- - "Cited By (since 1996): 89" - "Export Date: 24 October 2012" - "CODEN: NEOPF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Marc Rosenblum
    373 Rosenblum
  2. Eric Holland
    224 Holland
  3. Jason A Koutcher
    268 Koutcher
  4. Xiaoyi Hu
    8 Hu