Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels.
Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a full-length protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.
Satriano
J
J
Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego and Veterans Affairs Medical Center, La Jolla, California 92161, USA. jsatriano@ucsd.edu
Matsufuji
S
S
Murakami
Y
Y
Lortie
M J
MJ
Schwartz
D
D
Kelly
C J
CJ
Hayashi
S
S
Blantz
R C
RC
D016475:3T3 Cells; D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002262:Carboxy-Lyases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D018965:Frameshifting, Ribosomal; D006801:Humans; D051379:Mice; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D011700:Putrescine / Q000494:pharmacology; D051381:Rats
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D000376:Agmatine; D002262:Carboxy-Lyases; C019722:arginine decarboxylase; D011700:Putrescine