AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling

Markus J. Riemenschneider, Rebecca Betensky, Saskia M. Pasedag, David N. Louis

Research output: Contribution to journalArticle

Abstract

Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.

Original languageEnglish (US)
Pages (from-to)5618-5623
Number of pages6
JournalCancer Research
Volume66
Issue number11
DOIs
StatePublished - Jun 1 2006

Fingerprint

Ribosomal Protein S6 Kinases
Sirolimus
Glioblastoma
S 6
Apoptosis
Phosphorylation
Neoplasms
Proto-Oncogene Proteins c-akt
Caspase 3
Cell Cycle
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. / Riemenschneider, Markus J.; Betensky, Rebecca; Pasedag, Saskia M.; Louis, David N.

In: Cancer Research, Vol. 66, No. 11, 01.06.2006, p. 5618-5623.

Research output: Contribution to journalArticle

Riemenschneider, Markus J. ; Betensky, Rebecca ; Pasedag, Saskia M. ; Louis, David N. / AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. In: Cancer Research. 2006 ; Vol. 66, No. 11. pp. 5618-5623.
@article{e4c2e0d855804fbc952d617e5c37a687,
title = "AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling",
abstract = "Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.",
author = "Riemenschneider, {Markus J.} and Rebecca Betensky and Pasedag, {Saskia M.} and Louis, {David N.}",
year = "2006",
month = "6",
day = "1",
doi = "10.1158/0008-5472.CAN-06-0364",
language = "English (US)",
volume = "66",
pages = "5618--5623",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling

AU - Riemenschneider, Markus J.

AU - Betensky, Rebecca

AU - Pasedag, Saskia M.

AU - Louis, David N.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.

AB - Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=33745260930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745260930&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-0364

DO - 10.1158/0008-5472.CAN-06-0364

M3 - Article

C2 - 16740698

AN - SCOPUS:33745260930

VL - 66

SP - 5618

EP - 5623

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 11

ER -