5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors.
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-x(L) 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.
Serafeim
Adamantios
A
MRC Centre for Immune Regulation and the Department of Pharmacology, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
Grafton
Gillian
G
Chamba
Anita
A
Gregory
Christopher D
CD
Blakely
Randy D
RD
Bowery
Norman G
NG
Barnes
Nicholas M
NM
Gordon
John
J
D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015283:Citalopram / Q000494:pharmacology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D020169:Caspases; D015283:Citalopram; D004273:DNA, Neoplasm; D005473:Fluoxetine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human