Publication Date:
2007-11-16
Description:
Cyclic AMP (cAMP) potentiates glucocorticoid (GC) induced apoptosis in lymphoid cells but the mechanisms associated with these effects are unclear. We previously showed that cAMP inhibits PI3K/AKT activity and that in diffuse large B-cell lymphomas (DLBCL) overexpression of the phosphodiesterase 4B (PDE4B) blocks these effects. Recently, high AKT/mTOR activity was implicated in the GC resistance found in acute lymphoid leukemia (ALL) and rapamycin shown to modulate these effects. Therefore, we hypothesized that cAMP enhances GC responses by down-modulating the AKT/mTOR pathway and that PDE4B, by blunting these inhibitory effects, is at the center of GC resistance (and rapamycin activity) in DLBCL. If this notion is accurate, PDE4B expression may impinge on the same genes and pathways that control GC response in malignant lymphocytes. To test this idea, we used gene set enrichment analysis (GSEA) and found a marked association between gene sets of DLBCLs defined by high or low PDE4B expression and ALLs classified by their resistance or sensitivity to GC-induced apoptosis(p and FDR =.014). To further our investigation, we created PDE4B gain or loss of function models in DLBCL cell lines. We reconstituted PDE4B expression (wild-type [WT] or phosphodiesterase inactive [PI] mutant) in the PDE4B-null DHL6 cell line and constitutively expressed a PDE4B-specific RNAi, which decreased this gene expression 14-fold, in the PDE4B-high cell line Ly3 (Ly3Ri). The functional consequences of these changes were confirmed by measuring the intra-cellular levels of cAMP and further validated in cell proliferation assays. DHL6-PDE4B-WT cells became ∼ 50% more resistant to the inhibitory effects of cAMP (forskolin - 10μM) than their PI counterpart (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
