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A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells
Author(s) -
Matsuoka Yumiko,
Nagahara Yukitoshi,
Ikekita Masahiko,
Shinomiya Takahisa
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705182
Subject(s) - dephosphorylation , protein kinase b , p70 s6 kinase 1 , kinase , microbiology and biotechnology , apoptosis , biology , protein phosphatase 2 , okadaic acid , phosphatase , jurkat cells , pi3k/akt/mtor pathway , phosphorylation , chemistry , cancer research , biochemistry , signal transduction , immunology , t cell , immune system
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. 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. FTY720‐induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3′‐kinase (PI 3‐kinase) pathway inhibition. FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL‐1. BALL‐1 cells were resistant to FTY720‐induced apoptosis. Okadaic acid (OA) inhibited the FTY720‐induced dephosphorylation of Akt and p70 S6k , suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. OA partially inhibited FTY720‐induced caspase‐3 activation. PP2A or PP2A‐like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 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.British Journal of Pharmacology (2003) 138 , 1303–1312. doi: 10.1038/sj.bjp.0705182