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Comparative analysis of wild‐type and cAMP‐deathless S49 lymphoma cells identifies genes and pathways of cAMP/PKA‐promoted apoptosis

The second messenger cAMP acts via protein kinase A (PKA) to induce apoptosis by mechanisms that are poorly understood. Here, we assessed a role for mitochondria and analyzed gene expression in cAMP/PKA‐promoted apoptosis by comparing wild‐type (WT) S49 lymphoma cells and the S49 variant, D‐ (cAMP‐deathless), which lacks cAMP‐promoted apoptosis but that has WT levels of PKA activity as well as cAMP‐promoted G1 growth arrest. Treatment of WT, but not D‐, S49 cells with 8‐CPT‐cAMP for 24 h induced loss of mitochondrial membrane potential, mitochondrial release of cytochrome c and Smac and increase in caspase‐3 activity. Gene expression analysis (using Affymetrix 430 2.0 Arrays) revealed that WT and D‐ cells incubated with 8‐CPT‐cAMP have similar, but non‐identical, extents of cAMP‐regulated gene expression at 2h (~800 transcripts) and 6h (~1000 transcripts) (|Fold|>2, P<0.06); by contrast, at 24h ~2500 and ~1100 transcripts were changed in WT and D‐ cells, respectively. WT and D‐cells differed in CREB phosphorylation, expression of the transcriptional inhibitor Icer and cAMP‐regulated expression of genes in the Inhibitor of apoptosis (IAP) and Bcl families. We conclude that cAMP/PKA‐promoted apoptosis of lymphoid cells occurs via mitochondrial‐mediated events and that such apoptosis likely involves gene networks in multiple biochemical pathways. (Supported by the Leukemia and Lymphoma Society and the NIH).