MRP4/ABCC4 expression is regulated by histamine in acute myeloid leukemia cells, determining cAMP efflux

Intracellular cAMP (i‐cAMP) levels play an important role in acute myeloid leukemia (AML) cell proliferation and differentiation. Its levels are the result of cAMP production, degradation, and exclusion. We have previously described histamine H2 receptors and MRP4/ABCC4 as two potential targets for AML therapy. Acting through histamine H2 receptors, histamine increases cAMP production/synthesis, while MRP4/ABCC4 is responsible for the exclusion of this cyclic nucleotide. In this study, we show that histamine treatment induces MRP4/ABCC4 expression, augmenting cAMP efflux, and that histamine, in combination with MRP inhibitors, is able to reduce AML cell proliferation. Histamine, through histamine H2 receptor, increases i‐cAMP levels and induces MRP4 transcript and protein levels in U937, KG1a, and HL‐60 cells. Moreover, histamine induces MRP4 promoter activity in HEK293T cells transfected with histamine H2 receptor (HEK293T‐H2R). Our results support that the cAMP/Epac‐PKA pathway, and not MEK/ERK nor PI3K/AKT signaling cascades, is involved in histamine‐mediated upregulation of MRP4 levels. Finally, the addition of histamine potentiates the inhibition of U937, KG1a, and HL‐60 cell proliferation induced by MRP4 inhibitors. Our data highlight that the use of a poly‐pharmacological approach aimed at different molecular targets would be beneficial in AML treatment. Histamine, acting through histamine H2 receptor and via cAMP production, upregulates MRP4 levels causing an increase in cAMP efflux as part of a feedback mechanism. This prevents cAMP accumulation in the intracellular compartment which would otherwise inhibit AML cell proliferation. The addition of histamine potentiates the antiproliferative effect of MRP4 inhibitors. Our data highlight that the use of a poly‐pharmacological approach aimed at different molecular targets would be beneficial in AML treatment.