Independent Regulation of Ornithine Decarboxylase and S-Adenosylmethionine Decarboxylase in Methylthioadenosine Phosphorylase-deficient Malignant Murine Lymphoblasts1

The control of polyamine synthesis in neoplastia cells is com plex and incompletely understood. Using murine lymphoma cells deficient in methylthioadenosine (MTA) phosphorylase, we have analyzed the role of MTA in the regulation of ornithine decarboxylase and S-adenosylmethionine (SAM) decarboxylase, the two rate-limiting enzymes in the polyamine-biosynthetic pathway. The addition of MTA to the enzyme-deficient lymphoblasts in duced within 1 to 3 h an increase in the activities of both decarboxylases and an accompanying rise in putrescine and decarboxylated SAM levels. The ornithine decarboxylase inhibi tor a-difluoromethylomithine blocked the MTA-triggered accu mulation of putrescine but not decarboxylated SAM. In a recip rocal manner, the SAM decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) prevented the accretion of decarboxylated SAM but not putrescine. The MTA-induced rise in SAM decar boxylase and ornithine decarboxylase activities preceded by several hours changes in spermidine or spermine pools. How ever, MTA decreased the flux through the polyamine-synthetic pathway, as estimated by the incorporation of radioactive orni thine into spermine. Similar changes in polyamine metabolism were observed in a secondary mutant deficient in MTA phospho rylase, but resistant to MTA toxicity. These results suggest that the velocity of polyamine synthesis, or the concentration of MTA itself, may regulate ornithine decarboxylase and SAM decarbox ylase activities through separate, growth-independent mecha