Volume 19, No 3, Mar 2009
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 19 Issue 3, March 2009: 358-369
ORIGINAL ARTICLES
Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells
Tanvi S Jani1,*, Leila Gobejishvili2,*, Prachi T Hote1, Aditya S Barve2, Swati Joshi-Barve2, Giorgi Kharebava3, Jill Suttles4, Theresa Chen1, Craig J McClain1,2,5 and Shirish Barve1,2
1Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA;
2Department of Internal Medicine, University of Louisville Medical Center, Louisville, KY 40292, USA;
3Department of Neurological Surgery, KSCIRC, Louisville, KY 40292, USA;
4Department of Microbiology and Immunology, Louisville, KY 40292, USA;
5Louisville VA Medical Center, Louisville, KY 40292, USA
Correspondence: Shirish Barve,(shirish.barve@louisville.edu )
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-FLIPs 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.
Cell Research (2009) 19:358-369. doi: 10.1038/cr.2008.314; published online 2 December 2008
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