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Tumor Necrosis Factor- Sensitizes Prostate Cancer Cells to -Irradiation-induced Apoptosis¹

Division of Hematology/Oncology, Department of Medicine [K. K., C. B., E. P. G.], and Department of Biochemistry and Molecular Biology [S. S.], Lombardi Cancer Center, Georgetown University, Washington, DC 20007-2007

LNCaP prostate cancer cells are highly resistant to induction of programmed cell death by -irradiation and somewhat sensitive to the death-inducing effects of tumor necrosis factor (TNF)-. Simultaneous exposure of LNCaP cells to TNF- and 8 Gy of irradiation was synergistic and resulted in a 3-fold increase of apoptotic cells within 72 h compared to TNF- alone. It appeared that TNF- sensitized the cells to irradiation because, when cells were irradiated 24 h after exposure to TNF-, increased cell death was observed. In contrast, irradiation delivered 24 h prior to TNF- exposure did not result in more cell death than after TNF- alone. TNF- induced expression of its own mRNA, but TNF- mRNA induction was neither induced nor enhanced by irradiation. Activation of the transcription factor nuclear factor B can be induced by TNF- and has a modulating antiapoptotic effect. But enhancement of TNF--induced cell death by irradiation did not result from altered activation of nuclear factor B. TNF- treatment of LNCaP cells resulted in partial activation of caspase-8 and -6 but not caspase-3. There was only minimal poly(ADP-ribose) polymerase cleavage seen in LNCaP cells after exposure to both TNF- and irradiation at 72 h, a time when 60% of the cells were apoptotic. Experiments with peptide inhibitors of cysteine and serine proteases suggested that caspases were the predominant mediators of apoptosis induced by TNF- alone but that serine proteases contributed significantly to cell death induced by TNF- plus irradiation. TNF- increased production of ceramide in LNCaP cells 48 h after exposure. Although irradiation alone had no effect on ceramide production in LNCaP cells, TNF- plus irradiation induced significantly more ceramide than TNF- alone. Ceramide production did not occur immediately after exposure to TNF-, but rather was delayed such that ceramide levels were increased only 24 h after exposure to apoptotic stimuli. Moreover, nontoxic levels of exogenous C₂-ceramide sensitized LNCaP cells to irradiation similarly to TNF-, suggesting that one mechanism by which LNCaP cells were sensitized to irradiation was by increased intracellular ceramide. Hence, ceramide generation is a critical component in radiation-induced apoptosis in human prostate cancer cells. Inhibition of ceramide generation may provide a selective advantage in the development of radioresistance in prostate cancer.

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