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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2545-2553
NEOPLASIA
5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt
lymphoma cells: reversal by selective serotonin reuptake
inhibitors
Adamantios Serafeim,
Gillian Grafton,
Anita Chamba,
Christopher D. Gregory,
Randy D. Blakely,
Norman G. Bowery,
Nicholas M. Barnes, and
John Gordon
From the MRC Centre for Immune Regulation and the
Department of Pharmacology, The Medical School, University of
Birmingham; the School of Biomedical Sciences, University of Nottingham
Medical School, United Kingdom; and the Department of Pharmacology,
Center for Molecular Neuroscience, Vanderbilt University Medical
Center, Nashville, TN.
Serotonin (5-HT), a well-known neurotransmitter of the central
nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells
cultured in the presence of 5-HT exhibited marked suppression of DNA
synthesis that was accompanied by extensive apoptosis serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase
activation, and was accompanied by a decline in mitochondrial membrane
potential. BL cells that had drifted to a lymphoblastic group 3 phenotype were relatively resistant to these actions of serotonin, and
the forced ectopic expression of either bcl-2 or bcl-xL provided substantial protection from
5-HT-induced apoptosis. 5-HT receptor antagonists (SDZ205-557,
granisetron, methysergide) failed to inhibit serotonin-induced
apoptosis, whereas the selective serotonin reuptake inhibitors
(SSRI)fluoxetine (Prozac), paroxetine (Paxil), and citalopram
(Celexa)substantially blocked the monoamine actions. Western blot
analysis showed that BL cells expressed protein for the 5-HT
transporter, and transport assays confirmed active uptake of serotonin
by the cells. Unlike what was suggested for neuronal cells, there was
no evidence that intracellular oxidative metabolites were responsible
for the 5-HT-induced programmed death of BL cells. These data indicate
that serotonin drives apoptosis in biopsylike BL cells after its entry
through an active transport mechanism, and they suggest a novel
therapeutic modality for Burkitt lymphoma.
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