Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells.
Methionine adenosyltransferase II (MAT II) is a key enzyme in cellular metabolism and catalyzes the formation of S-adenosylmethionine (SAMe) from L-methionine and ATP. Normal resting T lymphocytes have minimal MAT II activity, whereas activated proliferating T lymphocytes and transformed T leukemic cells show significantly enhanced MAT II activity. This work was carried out to examine the role of MAT II activity and SAMe biosynthesis in the survival of leukemic T cells. Inhibition of MAT II and the resultant decrease in SAMe levels enhanced expression of FasL mRNA and protein, and induced DISC (Death Inducing Signaling Complex) formation with FADD (Fas-associated Death Domain) and procaspase-8 recruitment, as well as concomitant increase in caspase-8 activation and decrease in c-FLIP(s) levels. Fas-initiated signaling induced by MAT II inhibition was observed to link to the mitochondrial pathway via Bid cleavage and to ultimately lead to increased caspase-3 activation and DNA fragmentation in these cells. Furthermore, blocking MAT 2A mRNA expression, which encodes the catalytic subunits of MAT II, using a small-interfering RNA approach enhanced FasL expression and cell death, validating the essential nature of MAT II activity in the survival of T leukemic cells.
Jani
Tanvi S
TS
Department of Pharmacology and Toxicology, University of Louisville Medical Center, 511 S. Floyd, Louisville, KY 40202, USA.
Gobejishvili
Leila
L
Hote
Prachi T
PT
Barve
Aditya S
AS
Joshi-Barve
Swati
S
Kharebava
Giorgi
G
Suttles
Jill
J
Chen
Theresa
T
McClain
Craig J
CJ
Barve
Shirish
S
D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003515:Cycloleucine / Q000494:pharmacology; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors*; D009500:Neutralization Tests; D012436:S-Adenosylmethionine / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D003515:Cycloleucine; D012436:S-Adenosylmethionine; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase; D053148:Caspase 3; D053181:Caspase 8