AGMATINE SUPPRESSES PROLIFERATION BY FRAMESHIFT INDUCTION OF ANTIZYMEAND ATTENUATION OF CELLULAR POLYAMINE LEVELS

Polyamines are required for entry and progression of the cell cycle. A s such, augmentation of polyamine levels is essential for cellular tra nsformation. Polyamines are autoregulated through induction of antizym e, which represses both the rate-limiting polyamine biosynthetic enzym e ornithine decarboxylase and cellular polyamine transport. In the pre sent 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 su ppressing 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 o f antizyme mRNA to produce a full-length protein and (b) suppression o f agmatine-dependent inhibitory activity by either anti-antizyme IgG o r antizyme inhibitor. Furthermore, agmatine administration depletes in tracellular polyamine levels to suppress cellular proliferation in a t ransformed cell lime. This suppression is reversible with polyamine su pplementation. 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 growt h.