Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger

Abstract

The second messenger cyclic AMP (cAMP) can either stimulate or inhibit programmed cell death (apoptosis). Here, we review examples of cell types that show pro-apoptotic or anti-apoptotic responses to increases in cAMP. We also show that cells can have both such responses, although predominantly having one or the other. Protein kinase A (PKA)-promoted changes in phosphorylation and gene expression can mediate pro-apoptotic responses, such as in murine S49 lymphoma cells, based on evidence that mutants lacking PKA fail to undergo cAMP-promoted, mitochondria-dependent apoptosis. Mechanisms for the anti-apoptotic response to cAMP likely involve Epac (Exchange protein activated by cAMP), a cAMP-regulated effector that is a guanine nucleotide exchange factor (GEF) for the low molecular weight G-protein, Rap1. Therapeutic approaches that activate PKA-mediated pro-apoptosis or block Epac-mediated anti-apoptotisis may provide a means to enhance cell killing, such as in certain cancers. In contrast, efforts to block PKA or stimulate Epac have the potential to be useful in diseases settings (such as heart failure) associated with cAMP-promoted apoptosis.

Figure 1. cAMP can both stimulate and blunt apoptosis in S49 lymphoma cells

Wild-type S49 cells were incubated with 100μM CPT-cAMP, 500ng Anti-Fas or the combination of CPT-cAMP and Anti-Fas for 6h and 24h and then assayed for apoptosis (Annexin-V binding; left panel) or caspase 3 activity (determined using a colorometric assay kit from EMD; right panel). The results shown are from 3 separate experiments. *p<0.05, ** p<0.01 compared to control (0h), ## p<0.01 compared to anti-Fas alone by t-test analysis. Note that CPT-cAMP blunts Annexin V binding and caspase 3 activity induced by anti-Fas treatment at 6 hr but this blunting is lost by 24h and that CPT-cAMP increases caspase 3 activity at 24 hr as a prelude to apoptosis (Zhang and Insel, 2004; Zhang et al, 2008b).