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Inhibition of c-Jun-N-terminal-Kinase Sensitizes Tumor Cells to CD95-Induced Apoptosis and Induces G₂/M Cell Cycle Arrest

Department of Internal Medicine II, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany

Requests for reprints: Sören T. Eichhorst, Department of Internal Medicine II, University Hospital Grosshadern, Ludwig-Maximilians-University, Folab B 5 E01 308, Marchioninistrasse 15, D-81377 Munich, Germany. Phone: 49-89-7095-3176; Fax: 49-221-3762556; E-mail: S.Eichhorst{at}gmail.com.

Loss of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun-N-terminal-kinases (JNK) have been implicated in stress-induced apoptosis, but may also contribute to survival signaling. Here we show that CD95-induced apoptosis is augmented by the JNK inhibitor SP600125 and small interfering RNA directed against JNK1/2. SP600125 potently inhibited methyl methane sulfonate–induced phosphorylation of c-Jun, but had minimal effect on apoptosis alone. In contrast, it strongly enhanced CD95-mediated apoptosis in six of eight tumor cell lines and led to a G₂/M phase arrest in all cell lines. SP600125 enhanced cleavage of caspase 3 and caspase 8, the most upstream caspase in the CD95 pathway. JNK inhibition up-regulates p53 and its target genes p21^Cip1/Waf1 and CD95. However, although HCT116 p53^–/– cells and p21^+/+ cells were less sensitive to CD95 stimulation than their p53^+/+ and p21^–/– counterparts, p53 and p21 were not involved in the JNK-mediated effect. JunD, which was described to be protective in tumor necrosis factor–induced apoptosis, was not regulated by JNK inhibition on the protein level. When transcription was blocked by actinomycin D, JNK inhibition still enhanced apoptosis to a comparable extent. We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism.

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