Phorbol ester-induced promyelocytic leukemia cell adhesion to marrow stromal cells involves fibronectin specific alpha 5 beta 1 integrin receptors.
The human promyelocytic cell line NB4 exhibited a weak adhesion capacity for bone marrow-derived stromal cells and their extracellular matrices (5-15% of adherent cells). Adhesion was enhanced by pulse-treatment of cells with phorbolester (PMA 10(-7) M). Adhesion was induced within minutes, was fibronectin-specific, and affected up to 100% of the treated cells. This biological response to PMA resulted from the activation of protein kinase C (PKC), since PKC inhibitors (staurosporine, sphingosine, CGP 41251, and calphostin C) prevented the phenomenon. Phenotypical analysis of integrin receptor expression (particularly FN receptors VLA-4 and VLA-5) at the membrane of untreated or PMA-treated cells revealed that PMA induced no significant modification of the level of expression of these receptors. However, inhibition studies carried out with anti-VLA monoclonal antibodies demonstrated that the FN-specific adhesion triggered by PKC involved the alpha 5 beta 1 FN-specific receptors (VLA-5). We showed that the binding of NB4 cells to fibronectin was RGD-dependent. PMA-induced adhesion was not correlated to phosphorylation of the VLA-5 receptor. These findings may partially explain the malignant behaviour of these cells: The loss of their capacity to adhere to stromal cells may arrest differentiation and explain the large number of leukemic cells in the circulation.
Martin-Thouvenin
V
V
INSERM, U301, Hôpital Saint-Louis, Paris, France.
Gendron
M C
MC
Hogervorst
F
F
Figdor
C G
CG
Lanotte
M
M
D001853:Bone Marrow / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004789:Enzyme Activation / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011869:Radioligand Assay; D017469:Receptors, Fibronectin; D011971:Receptors, Immunologic / Q000378:metabolism*; D016029:Receptors, Very Late Antigen / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D005353:Fibronectins; D016023:Integrins; D017469:Receptors, Fibronectin; D011971:Receptors, Immunologic; D016029:Receptors, Very Late Antigen; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate