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J Biol Chem, Vol. 274, Issue 43, 30580-30588, October 22, 1999
§,¶,§
, and**
From the Departments of A variety of molecular changes occur during the
process of apoptosis. Much of the recent work has focused on changes in
critical cellular proteins, proteins necessary for the initiation and
continuation of the apoptotic process. Given the fact that numerous
membrane changes occur throughout the apoptotic process, we initiated
an investigation aimed at determining the major lipid changes that occurred during programmed cell death. When ionizing radiation was used
to initiate the apoptotic process in Jurkat cells, one of the
major changes that occurred within 24 h was an increase in a
species with a m/z of 572 as determined by
negative ion electrospray mass spectrometry. This particular mass ion
displayed high performance liquid chromatography characteristics of a
neutral lipid species. Further analysis by
collision-induced-dissociation tandem mass spectrometry indicated only
one daughter species indicative of a Cl adduct and therefore a parental
mass of 537. Comparison to a commercial C16 ceramide yielded identical
spectra by mass spectrometry (MS) and MS/MS analysis in the negative
ion mode. Increases in C16 ceramide levels occurred 2 h after
initiation of apoptosis by ionizing radiation, and its accumulation
paralleled apoptosis as determined by cellular morphology.
Interestingly, radiation-sensitive Jurkat cells displayed increased
levels of long term C16 ceramide accumulation, whereas
radiation-resistant K562 cells did not. These findings were supported
by increases in caspase-3 activity in Jurkat cells, whereas caspase-3
activity in K562 cells remained unchanged. C16 ceramide accumulation
and sensitivity to ionizing radiation was investigated further in a
melanoma cell line. Only those cells that were radiation sensitive
(approximately 70-75%) displayed increases in long term ceramide
accumulation. Taken together, these results indicated a correlation
between increases in C16 ceramide accumulation and radiation
sensitivity. Increases in long term C16 ceramide accumulation were also
seen in Fas-induced apoptosis, which occurred at time points greater
than 2 h. Analysis of mitochondrial modifications using the
mitochondrial probe nonyl acridine orange (NAO) indicated that initial
increases in C16 ceramide levels closely paralleled the decrease in
mitochondrial mass during Fas or radiation-induced apoptosis. Taken
together, these results support a role for C16 ceramide in the effector (mitochondrial) phase of apoptosis.
Surgery, University of Pittsburgh
School of Medicine, and the § University of Pittsburgh
Cancer Institute, Pittsburgh, Pennsylvania 15213, and the
¶ University of Pittsburgh Mass Spectrometry Facility, The
University of Pittsburgh Center for Biotechnology and Bioengineering,
Pittsburgh, Pennsylvania 15219
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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