Novel targets for leukemic differentiation therapy.

DAVIO CARLOS

CIUDAD AUTONOMA DE BUENOS AIRES

Workshop; Molecular Medicine Workshop; 2011

Ministerio de Ciencia Tecnología e Innovación Productiva en el marco de la visita de Directivos del Institute of Molecular Oncology Foundation.

G-protein coupled receptors (GPCRs) are the major membrane receptors that mediate extracellular signal transduction. These key signaling mediators are targeted by 25% of the therapeutic agents currently used in clinical treatments, which represents more than 50% of the pharmaceutical industry selling in the world. Although diverse extracellular signals activate GPCRs leading to an increase in cAMP, signal specificity results from accurate adjustments at different levels of the cAMP dependent pathway. Cyclic AMP was the first second messenger reported and since then numerous studies have shown its participation in many physiological and/or pathophysiological processes including cell cycle regulation. Cancer is one of the main causes of death worldwide and most of the drugs used in cancer therapeutics are highly toxic and/or lack specificity. In this context searching for novel specific targets to define new therapeutic strategies is crucial. Initially our investigations focused on the signaling mechanisms underlying the activation of histamine type 2 receptor (H2R) and the impact on leukemic cell proliferation and differentiation. Although cAMP is increased following H2R stimulation, cell differentiation fails to occur due to rapid receptor desensitization, supporting that leukemic cell differentiation depends not only on the duration but also on the intensity of cAMP signal. Recent studies from our laboratory show that cAMP effluxes from different myeloid leukemic cells further increasing the complexity of GPCRs coupled to the cAMP pathway. Our findings support that intracellular cAMP levels are regulated not only by cAMP dependent phosphodiesterases (PDEs) and receptor desensitization but also by multidrug resistance associated proteins (MRPs) which mediate cAMP efflux. Knock-down of MPR4 expression by shRNA reveals the critical role of this transporter in cAMP extrusion. Furthermore, both the pharmacological and the specific inhibition of MRP4 show that the intensity and duration of cAMP response inhibit proliferation and enhance differentiation in monocytes. Our findings confirm the relevant role of intracellular cAMP in leukemic cell maturation and further provide the first experimental evidence that MRP4 and cAMP efflux may represent a novel target for leukemia differentiation therapies. In the present dissertation the paradigmatic second messenger cAMP and its complex signal transduction network will be addressed with the future aim to define potential therapeutic targets for the development of safer and more efficacious drugs to be used in cancer clinical therapies. Current knowledge is challenging the main actors of the play Signal Transduction, starring cAMP. Unknown actors emerge as potential main characters with a promising future on stage.