Combined regulation of ornithine and S-adenosylmethionine decarboxylases by spermine and the spermine analogue N1 N12-bis(ethyl)spermine.
In the present study, the spermine (SPM) analogue N1N12-bis(ethyl)spermine (BESPM) is compared with SPM in its ability to regulate ornithine decarboxylase (ODC) and S-adenosyl-L-methionine decarboxylase (AdoMetDC) activities in intact L1210 cells and in the mechanism(s) by which this is accomplished. Unlike the comparable spermidine (SPD) analogue N1N8-bis(ethyl)spermidine, which regulates only ODC, BESPM suppresses both ODC and AdoMetDC activities. With 1 microM-SPM or -BESPM, near-maximal suppression of enzyme activity (i.e. less than 70%) was achieved after 2 h for ODC and 12 h for AdoMetDC. After such treatment, ODC activity fully recovered within 2-4 h, and that of AdoMetDC within 12 h, when cells were reseeded into drug-free media. It was deduced that an intracellular accumulation of BESPM or SPM equivalent to only approximately 200-450 pmol/10(6) cells was sufficient to fully invoke ODC regulatory mechanisms. Decreases in both enzyme activities after BESPM or SPM treatment were closely paralleled by concomitant decreases in the amount of enzyme protein. Since cellular ODC or AdoMetDC mRNA was not similarly decreased by either BESPM or SPM treatment, it was concluded that translational and/or post-translational mechanisms were probably responsible for enzyme regulation. In support of the former of these possibilities, it was demonstrated that both BESPM and SPM preferentially inhibited the translation in vitro of ODC and AdoMetDC relative to albumin in a reticulocyte-lysate system. On the basis of the consistent similarities between BESPM and SPM in all parameters studied, it is concluded that the analogue most likely acts by mechanisms identical with those by which SPM acts in suppressing polyamine biosynthesis.
Porter
C W
CW
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
Pegg
A E
AE
Ganis
B
B
Madhabala
R
R
Bergeron
R J
RJ
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007939:Leukemia L1210; D051379:Mice; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; D013096:Spermine; C052614:N(1), N(12)-diethylspermine; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase