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

Takayuki Ikezoe, Chie Nishioka, Kentaro Bandobashi, Yang Yang, Yoshio Kuwayama, Yoshihiro Adachi, Tamotsu Takeuchi, H. Phillip Koeffler, Hirokuni Taguchi

Research output: Contribution to journalArticlepeer-review

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, 48 h), 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 μM, 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 20 μM, 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.

Original languageEnglish (US)
Pages (from-to)673-682
Number of pages10
JournalLeukemia Research
Volume31
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

Keywords

  • 4E-BP-1
  • ATL
  • Akt
  • PI3K
  • mTOR
  • p70S6K

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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