Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis

• Published in: Blood Vol. 101; no. 8; pp. 3174 - 3180
• Main Authors: Jones, Dylan T., Ganeshaguru, Kanagasabai, Anderson, Robert J., Jackson, Trevor R., Bruckdorfer, K. Richard, Low, Sylvia Y., Palmqvist, Lars, Prentice, H. Grant, Hoffbrand, A. Victor, Mehta, Atul B., Wickremasinghe, R. Gitendra
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.2003; The Americain Society of Hematology
• Subjects: antagonists & inhibitors; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; B-Cell; Biological and medical sciences; Cell and Molecular Biology; Cell- och molekylärbiologi; Chemotherapy; Chlorambucil; Chlorambucil - pharmacology; Chromones; Chromones - pharmacology; Chronic; Confocal; Cultured; drug effects; Endocytosis; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Gamma Rays; Hematologi; Hematologic and hematopoietic diseases; Hematology; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytic; Medical sciences; Microscopy; Microscopy, Confocal; Morpholines; Morpholines - pharmacology; pathology; pharmacology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinases - physiology; Phosphoinositide-3 Kinase Inhibitors; physiology; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; radiation effects; Radiation-Protective Agents; Radiation-Protective Agents - pharmacology; Recombinant Proteins; Recombinant Proteins - pharmacology; Serum Albumin; Serum Albumin - pharmacology; Signal Transduction; Signal Transduction - drug effects; Tumor Cells; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - radiation effects; Antineoplastic agent; Human; Treatment resistance; Enzyme; Transferases; Albumin; Malignant hemopathy; B-Lymphocyte; Radiotherapy; 1-Phosphatidylinositol 3-kinase; Chlorambucil; Alkylating agent; Chemotherapy; Chronic; Chronic lymphocytic leukemia; Lymphoproliferative syndrome; Apoptosis; EC 2.7.1.137
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-07-2143

Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin by chromatography on Cibacron blue–Sepharose or plasma from a subject with analbuminemia failed either to activate AKT or to protect CLL cells from chlorambucil-induced apoptosis. Both functions were restored by re-addition of albumin. The protective action of albumin as well as AKT activation was compromised by the binding of lipids. Fluorescence-activated cell sorter (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL cells. Accumulation of albumin in intracellular vesicles was also shown by confocal microscopy. Indirect inhibition of AKT activation by the phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of chlorambucil-induced killing by plasma albumin. The data suggest that activation of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and radiation-induced apoptosis. Strategies designed to block albumin-induced antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug action on CLL cells.