Anisomycin affects both pro- and antiapoptotic mechanisms in PC12 cells

Survival and differentiation of PC12 cells depend on the proper balance bet ween the activities of several mitogen-activated protein kinase (MAPK) path ways. We have previously shown that low, nontoxic doses of anisomycin stimu lated these MAPKs as well. as the expression of several early-response gene s and inhibited NC;F-induced neurite formation. In the present work we show that protein synthesis-inhibiting concentrations of anisomycin, in contras t, cause apoptosis of PC12 cells. To try to characterize the apoptosis-indu cing mechanisms of anisomycin we compared the signaling effects of subinhib itory and inhibitory drug concentrations. Anisomycin in a nontoxic dosis ac tivates the same MAPK pathways and early-response genes as in protein synth esis inhibiting concentrations. In contrast, while the subinhibitory anisom ycin treatment stimulates Akt and induces Bcl-2, two anti-apoptotic protein s, the translation-inhibiting concentration of the drug prevents these surv ival-promoting biochemical events. Anisomycin thus triggers both pro- and a nti-apoptotic processes in PC12 cells; stimulation of stress-responsive MAP K cascades is not sufficient to mediate apoptotic signaling: the inhibition of key antiapoptotic proteins appears to be more important for PC12 cell d eath by anisomycin treatment. (C) 2000 Academic Press.