Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis.
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.
Jones
Dylan T
DT
Department of Hematology, Royal Free and University College Medical School, London, United Kingdom.
Ganeshaguru
Kanagasabai
K
Anderson
Robert J
RJ
Jackson
Trevor R
TR
Bruckdorfer
K Richard
KR
Low
Sylvia Y
SY
Palmqvist
Lars
L
Prentice
H Grant
HG
Hoffbrand
A Victor
AV
Mehta
Atul B
AB
Wickremasinghe
R Gitendra
RG
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002699:Chlorambucil / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005720:Gamma Rays; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011837:Radiation-Protective Agents / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012709:Serum Albumin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D002699:Chlorambucil; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D012709:Serum Albumin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human