Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors

Methods Mol Biol. 2012;821:349-59. doi: 10.1007/978-1-61779-430-8_22.

Abstract

Amplification of the gene encoding the epidermal growth factor receptor (EGFR) occurs commonly in glioblastoma (GBM), leading to activation of downstream kinases, including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). A serine-threonine kinase, mTOR controls cell growth by regulating mRNA translation, metabolism, and autophagy; acting as both a downstream effector and upstream regulator of PI3K. These signaling functions are distributed between at least two distinct complexes, mTORC1 and mTORC2 with respect to pathway specificity. We have investigated mTOR signaling in glioma cells with the allosteric mTORC1 inhibitor rapamycin, the mTORC1/2 inhibitor Ku-0063794, a dual PI3K/mTORC1/2 kinase inhibitor PI-103, and siRNA against raptor, rictor, or mTOR, and evaluated the value of mTOR inhibitors for the treatment of glioblastoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • ErbB Receptors / metabolism
  • Furans / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / enzymology*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Morpholines / pharmacology
  • Multiprotein Complexes
  • Oncogene Protein v-akt / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / antagonists & inhibitors*
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*

Substances

  • Adaptor Proteins, Signal Transducing
  • CRTC2 protein, human
  • Carrier Proteins
  • Furans
  • Morpholines
  • Multiprotein Complexes
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proteins
  • Pyridines
  • Pyrimidines
  • RICTOR protein, human
  • RNA, Small Interfering
  • RPTOR protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Transcription Factors
  • Ku 0063794
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Mechanistic Target of Rapamycin Complex 1
  • Oncogene Protein v-akt
  • Sirolimus