Inhibition of lymphocyte function associated antigen 1 by LFA878 induces apoptosis in multiple myeloma cells and is associated with downregulation of the focal adhesion kinase/phosphatidylinositol 3 kinase/Akt pathway.
Multiple myeloma (MM) is still an incurable disease and adhesion of MM cells to bone marrow stromal cells is one of the hallmarks of the disease. Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule that mediates lymphocyte adhesion, but its role in MM is only poorly understood. The aim of the presented study was to improve knowledge on LFA-1 and associated pathways in MM for the development of molecular targeted therapies. We demonstrate that LFA-1 is expressed in U266, RPMI-8226, OPM-2, and NCI-H929 MM cell lines and in primary cells of eight tested patients. The LFA-1 inhibitor LFA878 induces apoptosis in all four cell lines as revealed by annexin V staining and caspase 3 cleavage. Apoptosis is not hampered by adhesion to stromal cells. Additionally, the soluble ligand, intracellular adhesion molecule 1 (ICAM-1), which is increased in the serum of MM patients, does not protect from melphalan-induced apoptosis. Western blots demonstrate downregulation of FAK, PI3-K, and Akt upon LFA878 treatment. Additionally, sequential inhibition of the pathway by simultaneous application of Src family kinase or PI3-K inhibitors significantly increases LFA878 induced apoptosis. We conclude that LFA-1/FAK/PI3-K/Akt is a survival pathway in MM and that targeted inhibition may provide new therapeutic options.
Schmidmaier
Ralf
R
Department of Hematology and Oncology, Medizinische Klinik Innenstadt, Abteilung Hämatologie und Onkologie, Klinikum der Universität München, D-80336 München, Germany. ralf.schmidmaier@med.uni-muenchen.de
Mandl-Weber
Sonja
S
Gaul
Leander
L
Baumann
Philipp
P
Bumeder
Irmgard
I
Straka
Christian
C
Emmerich
Bertold
B
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009281:Naphthalenes / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects