FTY720, a novel immunosuppressive agent, induces apoptosis in human glioma cells.
FTY720, a metabolite from Isaria sinclairii, has been developed to be a potent immunosuppressive drug with induction of apoptosis in T cells and several cell lines. We investigated whether FTY720 induces apoptosis in human glioma cell lines, since they are relatively resistant to multiple apoptotic stimuli. In human glioma cells including T98G, FTY720 induced apoptosiswith ED50 between 1 to 10 microg/ml, while etoposidedid not induce apoptosis at the same doses. Among the caspase family proteases, mainly caspase-6 was activated during the apoptosis by FTY720 but not etoposide. In addition, FTY720 caused tyrosine dephosphorylation of FAK and did not activate a FAK-PI3-kinase survival pathway. This was confirmed also by the observation that orthovanadate prevented FTY720-induced dephosphorylation of FAK and inhibited FTY720-induced cell death. We assumed that FTY720 induced FAK dephosphorylation and cut off the FAK-PI3-kinase pathway resulting in the induction of apoptosis via caspase-6 activation in these glioma cells.
Sonoda
Y
Y
Department of Biochemistry and Immunology, Kyoritsu College of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo 105, Japan.
Yamamoto
D
D
Sakurai
S
S
Hasegawa
M
M
Aizu-Yokota
E
E
Momoi
T
T
Kasahara
T
T
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine / Q000031:analogs & derivatives; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D005047:Etoposide; D000068876:Fingolimod Hydrochloride; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D011409:Propylene Glycols; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D014443:Tyrosine; D014638:Vanadates; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C496050:PTK2 protein, human; C505407:CASP3 protein, human; C505514:CASP6 protein, human