Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase.
The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in lambda-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.
Forshell
TachaZi Plym
TP
Department of Molecular Biology, Umeå University, Sweden.
Rimpi
Sara
S
Nilsson
Jonas A
JA
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D003514:Cyclohexylamines / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D016271:Proto-Oncogene Proteins c-myc; C059116:4-methylcyclohexylamine; D011436:Spermidine Synthase