title: 5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors.
abstract: 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.
authors.affiliation: MRC Centre for Immune Regulation and the Department of Pharmacology, Medical School, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Serafeim
authors.forename: Gillian
authors.initials: G
authors.lastname: Grafton
authors.forename: Anita
authors.initials: A
authors.lastname: Chamba
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gregory
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Norman G
authors.initials: NG
authors.lastname: Bowery
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
authors.forename: John
authors.initials: J
authors.lastname: Gordon
mesh_terms: 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
chemical_list: 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