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Experimental Therapeutics |
Department of Biochemistry and Molecular Biology [V. E. N., O. C., S. S.], and Division of Hematology/Oncology, Department of Medicine [K. K., E. P. G.], Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, and Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 20892 [L. C. E., S. M.]
Ceramide has been implicated as an important component of
radiation-induced apoptosis of human prostate cancer cells. We examined
the role of the sphingolipid metabolites—ceramide, sphingosine, and
sphingosine–1-phosphate—in susceptibility to radiation-induced
apoptosis in prostate cancer cell lines with different sensitivities to
-irradiation. Exposure of radiation-sensitive TSU-Pr1 cells to 8-Gy
irradiation led to a sustained increase in ceramide, beginning after
12 h of treatment and increasing to 2.5- to 3-fold within 48 h. Moreover, irradiation of TSU-Pr1 cells also produced a marked and
rapid 50% decrease in the activity of sphingosine kinase, the enzyme
that phosphorylates sphingosine to form sphingosine-1-phosphate. In
contrast, the radiation-insensitive cell line, LNCaP, had sustained
sphingosine kinase activity and did not produce elevated ceramide
levels on 8-Gy irradiation. Although LNCaP cells are highly
resistant to -irradiation-induced apoptosis, they are sensitive
to the death-inducing effects of tumor necrosis factor 
,
which also increases ceramide levels in these cells (K. Kimura
et al., Cancer Res., 59: 1606–1614,
1999). Moreover, we found that although irradiation alone did not
increase sphingosine levels in LNCaP cells, tumor necrosis factor
plus irradiation induced significantly higher sphingosine levels and
markedly reduced intracellular levels of sphingosine-1-phosphate. The
elevation of sphingosine levels either by exogenous sphingosine or by
treatment with the sphingosine kinase inhibitor
N,N-dimethylsphingosine induced apoptosis
and also sensitized LNCaP cells to -irradiation-induced apoptosis.
Our data suggest that the relative levels of sphingolipid metabolites
may play a role in determining the radiosensitivity of prostate cancer
cells, and that the enhancement of ceramide and sphingosine generation
could be of therapeutic value.
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