Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 60; no. 16; pp. 4468 - 4474
• Main Authors: NAVA, V. E, CUVILLIER, O, EDSALL, L. C, KIMURA, K, MILSTIEN, S, GELMANN, E. P, SPIEGEL, S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2000
• Subjects: Ageing, cell death; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis - radiation effects; Biological and medical sciences; Caspases - metabolism; Cell physiology; Ceramides - metabolism; Ceramides - physiology; Enzyme Activation; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Male; Medical sciences; Molecular and cellular biology; Nephrology. Urinary tract diseases; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Phosphotransferases (Alcohol Group Acceptor) - physiology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - radiotherapy; Radiation Tolerance - drug effects; Radiation Tolerance - physiology; Radiation-Sensitizing Agents - pharmacology; Sphingomyelin Phosphodiesterase - pharmacology; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacology; Sphingosine - physiology; Tumor Cells, Cultured - radiation effects; Tumors of the urinary system; Urinary tract. Prostate gland; Antineoplastic agent; Radiosensitivity; Prostate disease; Metabolite; Phospholipid; Gamma irradiation; Established cell line; Ceramide; Mechanism of action; Male genital diseases; Tumor cell; Tumor necrosis factor α; Human; Urinary system disease; Enzyme; Transferases; Sphingolipid; Malignant tumor; In vitro; Sensitivity resistance; Cell death; Protein kinase; Prostate; Sphingosin; Apoptosis
• ISSN: 0008-5472

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 gamma-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 gamma-irradiation-induced apoptosis, they are sensitive to the death-inducing effects of tumor necrosis factor alpha, 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 alpha 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 gamma-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.