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Cholinergic Machinery as Relevant Target in Acute Lymphoblastic T Leukemia

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Cholinergic Machinery as Relevant Target in Acute Lymphoblastic T Leukemia

Oxana Dobrovinskaya et al. Front Pharmacol.

Abstract

Various types of non-neuronal cells, including tumors, are able to produce acetylcholine (ACh), which acts as an autocrine/paracrine growth factor. T lymphocytes represent a key component of the non-neuronal cholinergic system. T cells-derived ACh is involved in a stimulation of their activation and proliferation, and acts as a regulator of immune response. The aim of the present work was to summarize the data about components of cholinergic machinery in T lymphocytes, with an emphasis on the comparison of healthy and leukemic T cells. Cell lines derived from acute lymphoblastic leukemias of T lineage (T-ALL) were found to produce a considerably higher amount of ACh than healthy T lymphocytes. Additionally, ACh produced by T-ALL is not efficiently hydrolyzed, because acetylcholinesterase (AChE) activity is drastically decreased in these cells. Up-regulation of muscarinic ACh receptors was also demonstrated at expression and functional level, whereas nicotinic ACh receptors seem to play a less important role and not form functional channels in cells derived from T-ALL. We hypothesized that ACh over-produced in T-ALL may act as an autocrine growth factor and play an important role in leukemic clonal expansion through shaping of intracellular Ca(2+) signals. We suggest that cholinergic machinery may be attractive targets for new drugs against T-ALL. Specifically, testing of high affinity antagonists of muscarinic ACh receptors as well as antagomiRs, which interfere with miRNAs involved in the suppression of AChE expression, may be the first choice options.

Keywords: T leukemia; T lymphocyte; acetylcholine; acetylcholinesterase; calcium signaling; choline acetyltransferase; muscarinic receptor non-neuronal cholinergic system.

Figures

FIGURE 1
FIGURE 1
Current view on T cell NNCS in regulation of immune function. (A) Proposed paracrine and autocrine effect of T cell-derived ACh in T cell microenvironment. (B) Role of NNCS in Ca2+ signaling and gene expression in healthy T-lymphocyte. (A) TCR- and muscarinic (M1, 3, 5) receptor- triggered signaling pathways are cross-linked in T cells. In healthy T-cells, principle route of phospholipase C (PLCγ) activation upon recognition of antigen-presenting cell occurs via TCR/CD3 complex. TCR –generated signal is amplified by a co-receptor (CD4), which recruits Lck, a tyrosine kinase, phosphorylating several targets, including Z-chain protein kinase ZAP70, which phosphorylates LAT (linker for activation of T-cells), interacting with PLCγ. PLCγ may be activated through alternative mechanism related to T cell cholinergic system, where import of choline (Cho), synthesis of ACh and its secretion via yet unknown pathway results in paracrine/ autocrine activation of muscarinic receptors M1, M3 and/or M5. It follows by activation of trimeric G-protein (Gq11), whose subunit α activates PLCγ. PLCγ degrades phosphatidylinositol 4,5-bisphosphate (PIP2) into soluble IP3 and membrane bound diacylglycerol (DAG). Intracellular release of IP3 activates IP3 receptor-channel, mediating Ca2+-release from ER. Ca2+ depletion of reticulum is sensed by STIM1 of ER membrane, which promotes assembly of Orai subunits and formation of CRAC channel in the plasma membrane, the main route of capacitive Ca2+ entry, which considered to be principle Ca2+ influx channel in lymphocytes. CRAC-mediated Ca2+ influx is sustained, when membrane negative potential difference is maintained due to K+ efflux via a set of K+-selective channels, in healthy T-cells represented by voltage-dependent Kv1.3 channel and Ca2+-activated intermediate conductance K+ channel KCa3.1. Activation of calcineurin (CN) via Ca2+/calmodulin (CaM) complex occurs only upon prolonged intracellular Ca2+ increase. Principle target of CN is NFATs, heavily phosphorylated at the rest; its dephosphorylation make it permeable via nuclear pore. By entering nucleus, NFAT induces the transcription of several genes.
FIGURE 2
FIGURE 2
Hypothetical model of NNCS involvement in T leukemogenesis. (A) Autocrine and paracrine effect of ACh derived from T leukemic cell in specific leukemic niche in BM. (B) Network of signaling events in leukemic T lymphoblasts. It is suggested, that in absence of TCR/CD3 stimulation in leukemic T cells, elevated level of ACh production and autostimulation through M (1, 3, 5) receptors may play key role in signaling network. The sustained CRAC-mediated Ca2+ influx is maintained due to K+ efflux via a set of K+-selective channels: voltage-dependent Kv1.3 and small conductance KCa2.2; TWIK-related tandem pore K+ channel TRESK may be also recruited being activated by dephosphorylation by CN. Other abbreviations: NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells), PKC (protein kinase C), IL (interleukin), C-Fos (proto-oncogene, transcription factor), CHT1 (high-affinity choline transporter 1), CTL1-5 (intermediate-affinity choline-transporter-like proteins), ChAT (choline acetyltransferase), AcCoA (acetyl coenzyme A).

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