MRP4/ABCC4 expression is regulated by histamine in acute myeloid leukemia cells, determining cAMP efflux
Open Access
- 25 April 2020
- journal article
- research article
- Published by Wiley in The FEBS Journal
- Vol. 288 (1), 229-243
- https://doi.org/10.1111/febs.15344
Abstract
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.Keywords
Funding Information
- Agencia Nacional de Promoción Científica y Tecnológica (PICT2015‐2996, PICT2015‐2443, PICT2016‐1821, PICT2017‐2491)
- Universidad de Buenos Aires (UBACyT‐20020170100674BA)
This publication has 67 references indexed in Scilit:
- Optimizing survival outcomes with post‐remission therapy in acute myeloid leukemiaAmerican Journal of Hematology, 2019
- Differentiation therapy revisitedNature Reviews Cancer, 2017
- Acute Myeloid LeukemiaThe New England Journal of Medicine, 2015
- An ATRActive future for differentiation therapy in AMLBlood Reviews, 2015
- Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cellsHaematologica-The Hematology Journal, 2012
- Histamine dihydrochloride and low-dose interleukin-2 as post-consolidation immunotherapy in acute myeloid leukemiaExpert Opinion on Biological Therapy, 2009
- Differentiation therapy of leukemia: 3 decades of developmentBlood, 2009
- Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trialBlood, 2006
- Is there a role for postremission therapy in older adults with acute myelogenous leukemia (AML)?Leukemia, 2005
- Cell‐to‐Cell Mediated Inhibition of Natural Killer Cell Proliferation by Monocytes and its Regulation by Histamine H2‐ReceptorsScandinavian Journal of Immunology, 1991