Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR Academic Article uri icon

Overview

MeSH Major

  • Immunophilins
  • Neoplasms, Experimental
  • Phosphoric Monoester Hydrolases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein Kinase Inhibitors
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins

abstract

  • Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN(+/+) and PTEN(-/-) mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN(+/+) cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.

publication date

  • August 28, 2001

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC56958

Digital Object Identifier (DOI)

  • 10.1073/pnas.171076798

PubMed ID

  • 11504908

Additional Document Info

start page

  • 10314

end page

  • 9

volume

  • 98

number

  • 18