Pizzo DP, Ientile R, Colombatto S, Toninello A, Satriano J. The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis.
The arginine metabolite agmatine suppresses growth. Notably, this effect preferentially targets cells with high proliferative kinetics (Isome, et al, AJP, 2007). However, the mechanisms of this process have yet to be defined.Here we demonstrate via FACS analysis a dose dependent G1 phase cell cycle arrest with agmatine administration. Western blot evaluations of G1 cell cycle proteins demonstrate decreases in cyclin D1 expression, phosphorylation state of the retinoblastoma protein, and cyclin A expression. We observe induction of cyclin kinase inhibitors p16 and p21, but not p53.Agmatine administered to cultured cells results in neither necrosis nor apoptosis, as shown by DNA fragmentation and chromatin condensation assays. Unexpectedly, agmatine decreases the expression and activity of caspase‐3 in a dose and time dependent fashion. Furthermore, agmatine inhibits the induction of caspase‐3 activity in response to apoptotic mediators, camptothecin and 5‐fluorouricil.CONCLUSIONS: Agmatine confers resistance to apoptosis and can suppress proliferation via a p53 independent cell cycle arrest. Aberrant apoptosis and/or proliferation are common pathologic complications. As previously shown in an in vivo model of glomerulonephritis (Ishizuka, JASN, 2000), agmatine may be a candidate for adjunctive therapy in renal disease.Funding: NIH/NIDDK, VA
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