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mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor

Janine Masri1, Andrew Bernath, Jheralyn Martin

  • 1Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, California 91343-2099, USA.

Cancer Research
|December 20, 2007
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) is hyperactivated in gliomas, driving tumor growth and invasion. Elevated rictor levels increase mTORC2 activity, promoting oncogenic properties in glioma cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The mammalian target of rapamycin complex 2 (mTORC2) is a key kinase regulating cell growth and actin organization.
  • mTORC2 phosphorylates and activates Akt, a protein frequently activated in gliomas.
  • Elevated Akt activity in gliomas suggests a potential role for mTORC2 in glioma pathogenesis.

Purpose of the Study:

  • To investigate mTORC2 activity in glioma cell lines and primary tumor cells.
  • To determine the correlation between rictor expression and mTORC2 activity in gliomas.
  • To elucidate the functional role of mTORC2 hyperactivation in glioma development and progression.

Main Methods:

  • Assessed mTORC2 activity in glioma cells and normal brain tissue.
  • Quantified rictor protein and mRNA levels in glioma samples.
  • Utilized rictor overexpression and small interfering RNA (siRNA) knockdown in cell lines.
  • Performed soft agar assays, cell cycle analysis, and motility assays.
  • Conducted xenograft studies in mice.

Main Results:

  • mTORC2 activity was significantly elevated in glioma cells compared to normal brain tissue.
  • Rictor protein and mRNA levels were upregulated in gliomas, correlating with increased mTORC2 activity.
  • Rictor overexpression enhanced mTORC2 assembly and activity, leading to increased anchorage-independent growth, S-phase distribution, motility, and integrin expression.
  • Rictor knockdown inhibited these oncogenic phenotypes.
  • PKC alpha activity was modulated by rictor levels, consistent with mTORC2's role in actin organization.
  • Xenograft studies confirmed the role of increased mTORC2 activity in gliomagenesis and tumor growth.

Conclusions:

  • mTORC2 is hyperactivated in gliomas, primarily due to rictor overexpression.
  • This hyperactivation promotes critical oncogenic functions, including proliferation and invasion.
  • Targeting mTORC2, particularly rictor, may represent a therapeutic strategy for gliomas.

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