Abstract
Background: Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described herein the ability of ethoxyfagaronine (etxfag), a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V).Methods: Phosphorylation of fak and pyk2 were evaluated by immunoblotting. Labelled proteins were localized by confocal microscopy. PI 3-kinase activity was evaluated byin vitrokinase assay.Results: Subtoxic concentration of etxfag reduced L1210 cell adhesion to FN/V dependently of β1 integrin engagement. Etxfag impaired FN-dependent formation of β1 clustering without modifying β1 expression at the cell membrane. This was accompanied by a decrease of focal adhesion number, a diminution of fak and pyk2 phosphorylation at Tyr-576, Tyr-861 and Tyr-579, respectively leading to their dissociations from β1 integrin and inhibition of PI 3-kinase activity. Etxfag also induced a cell retraction accompanied by a redistribution of phosphorylated fak and pyk2 in the perinuclear region and lipid raft relocalization.Conclusion: Through its anti-adhesive potential, etxfag, combined with conventional cytotoxic drugs could be potentially designed as a new anti-leukemic drug.
Highlights
Leukemias are defined as uncontrolled proliferation and enhanced invasiveness of hematopoietic cells that fail to differentiate into mature blood cells
FN-CH/V corresponding to the sequence WQPPRARI (FN/V) peptide significantly enhanced in a timedependent manner L1210 cell adhesion as compared to BSA controls (Fig. 1a)
L1210 cell adhesion to FN/V was reduced with 5 mM EDTA and enhanced with 5 mM Mg2+ suggesting that divalent cations could be involved in L1210 cell adhesion to FN/V (Fig. 1b)
Summary
Leukemias are defined as uncontrolled proliferation and enhanced invasiveness of hematopoietic cells that fail to differentiate into mature blood cells. Acute lymphoblastic leukemia (ALL) originates from a single lymphoid progenitor and is characterized by an excessive egress of leukemic blasts from bone marrow (BM). Subsequent leukemic cell invasion of extramedullary sites require cell adhesion to extracellular matrix (ECM) proteins, ECM proteolysis, basement membrane crossing and migration into the surrounding tissues [1]. Hematopoietic cell interactions with BM proteins are largely mediated by integrin adhesion receptors that consist of ␣ and  integrin subunits [6]. Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described the ability of ethoxyfagaronine (etxfag), a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V)
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