S-adenosylhomocysteine as a physiological modulator of Apo-1-mediated apoptosis

APOI/Fas (CD95) Is a member of the tumor necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis In various cell types. Here we show that L929 cells, expressing human APO-1 treated with agonistic antibodies (anti-APO-1), elicit an early and transient Increase of S-adenosylhomocystelne (AdoHcy), a potent inhibitor of S-adenosyl- methionlne (AdoMet)-dependent methylatlon reactions. In contrast, anti-APO-1 did not Induce an AdoHcy increase In L929-APO-1 A4 cells expressing a C-terminally truncated APO-1 lacking part of the 'death domain' known to be required for the transduction of apoptotic signals. Addition of adenosine and D,i_-homocystelne also led to an Increase of cellular AdoHcy thus enhancing anti- APO-1-Induced killing of L929-APO-1 cells. Treatment with antl-APO-1 also Induced release of arachidonic acid from phospholipids: this effect was augmented by elevated levels of AdoHcy. In contrast, AdoHcy had only a minor effect on anti-APO-1-mediated DNA fragmentation. These findings suggest that AdoHcy functions as a physiological modulator of APO-1-mediated cell death in L929 cells and enhances antl-APO-1-induced cell killing at least partially by acting via the phosphollpase A2 pathway.