A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells.
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.
Matsuoka
Yumiko
Y
Division of Radio Isotopes and Biosafety Research, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8567, Japan.
Nagahara
Yukitoshi
Y
Ikekita
Masahiko
M
Shinomiya
Takahisa
T
D001773:Blood Cells / Q000473:pathology*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D066298:In Vitro Techniques; D007938:Leukemia / Q000097:blood* / Q000175:diagnosis*; D010766:Phosphorylation; D011409:Propylene Glycols / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism*
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine