Protein kinase A and Epac (Exchange Protein Activated by cAMP) are Pro‐and Anti‐Apoptotic Mediators, respectively, in Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL), which can be classified as "indolent" or "aggressive", is generally characterized by the accumulation of B‐cells. Increasing the level of cAMP can promote apoptosis of CLL cells but mechanisms for this pro‐apoptotic response are not known. The actions of cAMP are largely mediated by protein kinase A (PKA) and exchange protein activated by cAMP (Epac). We sought to investigate the role of these two downstream mediators in cAMP‐induced apoptosis using CLL cells and EHEB cells, a CLL‐cell line. Activation of PKA by N6‐ Phenyladenosine‐cAMP (50 μM, 48 hr) and 8‐Chloro‐cAMP (50 μM, 48 hr) both induced apoptosis of CLL cells and decreased the proliferation of EHEB cells. In contrast, Epac activation by 8‐pCPT‐2Me‐cAMP (50 μM, 48 hr), which stimulated Rap‐1 activation, protected the CLL from spontaneous apoptosis and increased EHEB proliferation. Further analysis revealed that CLL cells (isolated from both indolent and aggressive patients) have increased Epac‐1 mRNA and protein expression compared to normal PBMC and normal B‐cells. These data suggest that increased expression of Epac‐1 contributes to anti‐apoptosis in CLL. Efforts to decrease the expression and function of Epac‐1 may thus be beneficial for the treatment of CLL by increasing the pro‐apoptotic effects of drugs that act through raising cAMP and activating PKA. Supported by the Lymphoma and Leukemia Society and NIH.