Ap(4)A induces apoptosis in human cultured cells

Diadenosine oligophosphates (Ap(n)A) have been proposed as intracellular an d extracellular signaling molecules in animal cells. The ratio of diadenosi ne 5',5'''-P-1,P-3-triphosphate to diadenosine 5',5'''-P-1,P-4-tetraphospha te (Ap(3)A/Ap(4)A) is sensitive to the cellular status and alters when cult ured cells undergo differentiation or are treated with interferons. In cell s undergoing apoptosis induced by DNA topoisomerase II inhibitor VP16, the concentration of Ap(3)A decreases significantly while that of Ap(4)A increa ses. Here, we have examined the effects of exogenously added Ap(3)A and Ap( 4)A on apoptosis and morphological differentiation. Penetration of Ap(n) in to cells was achieved by cold shock. Ap(4)A at 10 mu M induced programmed c ell death in human HL60, U937 and Jurkat cells and mouse VMRO cells and thi s effect appeared to require Ap(4)A breakdown as hydrolysis-resistant analo gues of Ap(4)A were inactive, On its own, Ap(3)A induced neither apoptosis nor cell differentiation but did display strong synergism with the protein kinase C activators 12-deoxyphorbol-13-O-phenylacetate and 12-deoxy-phorbol -13-O-phenylacetate-20-acetate in inducing differentiation of HL60 cells. W e propose that Ap(4)A and Ap(3)A are physiological antagonists in determina tion of the cellular status: Ap(4)A induces apoptosis whereas Ap(3)A is a c o-inductor of differentiation. In both cases, the mechanism of signal trans duction remains unknown. (C) 1999 Federation of European Biochemical Societ ies.