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MRP4/ABCC4 expression is regulated by histamine in acute myeloid leukemia cells, determining cAMP efflux
Author(s) -
Rodríguez González Angela,
Sahores Ana,
DíazNebreda Antonela,
Yaneff Agustín,
Di Siervi Nicolás,
Gómez Natalia,
Monczor Federico,
Fernández Natalia,
Davio Carlos,
Shayo Carina
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15344
Subject(s) - histamine , histamine receptor , mapk/erk pathway , downregulation and upregulation , receptor , histamine h2 receptor , biology , protein kinase b , microbiology and biotechnology , histamine h1 receptor , signal transduction , hek 293 cells , myeloid leukemia , pharmacology , cancer research , medicine , biochemistry , gene , antagonist
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 H 2 receptors and MRP4/ABCC4 as two potential targets for AML therapy. Acting through histamine H 2 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 H 2 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 H 2 receptor (HEK293T‐H 2 R). 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.