A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells

Br J Pharmacol. 2003 Apr;138(7):1303-12. doi: 10.1038/sj.bjp.0705182.

Abstract

1. Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis. 2. Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time- and concentration-dependent manner. FTY720 also induced Bad (Ser(136)) and ribosomal p70S6 kinase (p70(S6k)) (Thr(389)) dephosphorylation. 3. FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3'-kinase (PI 3-kinase) pathway inhibition. 4. FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis. 5. Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70(S6k), suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. 6. OA partially inhibited FTY720-induced caspase-3 activation. 7. PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 8. Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Cells / pathology*
  • Fingolimod Hydrochloride
  • Humans
  • Immunosuppressive Agents
  • In Vitro Techniques
  • Leukemia / blood*
  • Leukemia / diagnosis*
  • Phosphorylation
  • Propylene Glycols / pharmacology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sphingosine / analogs & derivatives
  • U937 Cells / drug effects
  • U937 Cells / metabolism*

Substances

  • Immunosuppressive Agents
  • Propylene Glycols
  • Proto-Oncogene Proteins
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Fingolimod Hydrochloride
  • Sphingosine