Alpha particles induce apoptosis through the sphingomyelin pathway Journal Article

Authors: Seideman, J. H.; Stancevic, B.; Rotolo, J. A.; McDevitt, M. R.; Howell, R. W.; Kolesnick, R. N.; Scheinberg, D. A.
Article Title: Alpha particles induce apoptosis through the sphingomyelin pathway
Abstract: The sphingomyelin pathway involves the enzymatic cleavage of sphingomyelin to produce ceramide, a second messenger that serves as a key mediator in the rapid apoptotic response to various cell stressors. Low-linear energy transfer (LET) γ radiation can initiate this pathway, independent of DNA damage, via the cell membrane. Whether short-ranged, high-LET α particles, which are of interest as potent environmental carcinogens, radiotherapies and potential components of dirty bombs, can act through this mechanism to signal apoptosis is unknown. Here we show that irradiation of Jurkat cells with α particles emitted by the 225Ac-DOTA-anti-CD3 IgG antibody construct results in dose-dependent apoptosis. This apoptosis was significantly reduced by pretreating cells with cholesterol-depleting nystatin, a reagent known to inhibit ceramide signaling by interfering with membrane raft coalescence and ceramide-rich platform generation. The effects of nystatin on α-particle-induced apoptosis were related to disruption of the ceramide pathway and not to microdosimetry alterations, because similar results were obtained after external irradiation of the cells with a broad beam of collimated α particles using a planar 241Am source. External irradiation allowed for more precise control of the dosimetry and geometry of the irradiation, independent of antibody binding or cell internalization kinetics. Mechanistically consistent with these findings, Jurkat cells rapidly increased membrane concentrations of ceramide after external irradiation with an average of five α-particle traversals per cell. These data indicate that α particles can activate the sphingomyelin pathway to induce apoptosis. © 2011 by Radiation Research Society.
Keywords: signal transduction; controlled study; human tissue; dna damage; apoptosis; immunoglobulin g; isotope labeling; radiometry; antigen binding; immunoglobulin g antibody; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; concentration response; internalization; leukemia cell line; jurkat cells; ceramide; sphingomyelin; second messenger; alpha radiation; gamma radiation; alpha particles; actinium; actinium 225; linear energy transfer; microdosimetry; nystatin; cd3 antibody; cell disruption; sphingomyelins
Journal Title: Radiation Research
Volume: 176
Issue: 4
ISSN: 0033-7587
Publisher: Radiation Research Society  
Date Published: 2011-10-01
Start Page: 434
End Page: 446
Language: English
DOI: 10.1667/rr2472.1
PROVIDER: scopus
PMCID: PMC3185310
PUBMED: 21631289
Notes: --- - "Export Date: 2 November 2011" - "CODEN: RAREA" - "Source: Scopus"
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MSK Authors
  1. Michael R Mcdevitt
    118 Mcdevitt
  2. Richard N Kolesnick
    243 Kolesnick
  3. Jimmy A Rotolo
    31 Rotolo