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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-07-2143.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3174-3180
NEOPLASIA
Albumin activates the AKT signaling pathway and protects
B-chronic lymphocytic leukemia cells from chlorambucil- and
radiation-induced apoptosis
Dylan T. Jones,
Kanagasabai Ganeshaguru,
Robert J. Anderson,
Trevor R. Jackson,
K. Richard Bruckdorfer,
Sylvia Y. Low,
Lars Palmqvist,
H. Grant Prentice,
A. Victor Hoffbrand,
Atul B. Mehta, and
R. Gitendra Wickremasinghe
From the Departments of Hematology and Biochemistry and
Molecular Biology, Royal Free and University College Medical School,
London, United Kingdom; and the Institute of Laboratory
Medicine, Department of Clinical Chemistry, Sahlgrenska
University Hospital, Göteborg, Sweden.
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.
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