Inhibition of phosphatidylinositol 3-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway

Shahab Uddin*, Azhar Hussain, Khaled Al-Hussein, Leonidas C. Platanias, Kishor G. Bhatia

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

We examined the functional role of the phosphatidylinositol 3 -kinase pathway in the growth and survival of cell lines of T-cell origin. Pharmacological inhibition of PI3-kinase using LY294002 resulted in apoptosis of acute lymphoblastic T-cell leukemia (T-ALL) cell lines including CEM, Jurkat, and MOLT-4. On the other hand, the cutaneous T-cell lymphoma cell line HUT-78 was found to be refractory to LY294002- inducible apoptosis. Sensitivity or resistance to pharmacological inhibitors of PI3-kinase correlated with tumor suppressor PTEN gene expression, as sensitive T-ALL cells do not express PTEN and have high level of activated AKT, in contrast to HUT-78 cells. Our data demonstrate that inhibition of PI3-kinase results in dephosphorylation of AKT and partial inhibition of Bcl-xL expression in T-ALL cells, but not in HUT-78 cells. Interestingly, HUT-78 cells were also found to express higher levels of Bcl-xL protein as compared to T-ALL cells. Inhibition of PI3-kinase also induces release of cytochrome c from mitochondria and activation of caspase-3 and PARP in all T-ALL cell lines tested, but not in HUT-78 cells. Taken altogether, our data demonstrate that the PI3-kinase/AKT pathway plays a major role in the growth and survival of PTEN-null T-ALL cells, and identify this cascade as promising target for therapeutic intervention in acute T-cell leukemias.

Original languageEnglish (US)
Pages (from-to)932-938
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume320
Issue number3
DOIs
StatePublished - Jul 30 2004

Keywords

  • AKT/PKB
  • Apoptosis
  • Bcl-xL
  • Lymphoblastic T-cell leukemia
  • PTEN
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Inhibition of phosphatidylinositol 3<sup>′</sup>-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway'. Together they form a unique fingerprint.

Cite this