Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells

Leuk Res. 2007 May;31(5):673-82. doi: 10.1016/j.leukres.2006.08.001. Epub 2006 Sep 27.

Abstract

This study found that phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling was activated in human T-cell lymphotropic virus type I (HTLV-1)-infected leukemia cells. Rapamycin (1-100 nM, 48h), the inhibitor of mTOR and its analog RAD001 (1-100 nM, 48 h)-induced growth inhibition and G0/G1 cell cycle arrest of these cells in association with de-phosphorylation of p70S6K and 4E-BP-1, although IC50 was not achieved. Paradoxically, rapamycin-stimulated phosphorylation of Akt at Ser473. Blockade of Akt signaling by the PI3K inhibitor LY294002 (1-20 microM, 48 h) also resulted in the growth inhibition and G0/G1 cell cycle arrest of HTLV-1-infected cells, with IC50 ranging from 5 to 20muM, and it caused de-phosphorylation of p70S6K and 4E-BP-1. Of note, when rapamycin was combined with LY294002, rapamycin-induced phosphorylation of Akt was blocked, and the ability of rapamycin to induce growth arrest of HTLV-1-infected T-cells and suppress the p-p70S6K and p-4E-BP-1 proteins was potentiated. Moreover, both LY294002 and rapamycin down-regulated the levels of c-Myc and cyclin D1 proteins in these cells, and their combination further decreased levels of these cell cycle-regulating proteins. Taken together, longitudinal inhibition of PI3K/Akt/mTOR signaling represents a promising treatment strategy for individuals with adult T-cell leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins
  • Chromones / pharmacology*
  • Cyclin D
  • Cyclins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Human T-lymphotropic virus 1
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Leukemia-Lymphoma, Adult T-Cell / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / pathology*
  • Morpholines / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinases*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromones
  • Cyclin D
  • Cyclins
  • EIF4EBP1 protein, human
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • MYC protein, human
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Proto-Oncogene Proteins c-myc
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Sirolimus