Anisomycin activates JNK and sensitises DU 145 prostate carcinoma cells to Fas mediated apoptosis.
Treatment of the hormone refractory prostate cancer cell line DU 145 with sublethal concentrations of chemotherapeutic drugs has been reported to sensitise these cells to Fas mediated apoptosis. However, the mechanism by which this occurs has not been determined. Our group has shown that inhibition of JNK activity completely abrogates the effects of chemotherapeutic drugs. Using anisomycin, a potent JNK agonist, we have demonstrated a role for JNK in Fas mediated apoptosis in DU 145 cells. Inhibition of Caspase 8 and Caspase 9 completely inhibits this process which suggests that DU 145 cells require mitochondrial amplification of the Fas apoptotic signal. Furthermore, we have shown that inhibition of Fas mediated apoptosis is an early event in DU 145 cells, occurring upstream of Caspase 8 cleavage. It is hoped that identifying the target of JNK will allow novel therapies to be developed for the treatment of hormone refractory prostate cancer. Such therapies are especially important because no single or combined treatment to date has significantly prolonged survival in patients with hormone refractory prostate cancer.
Curtin
J F
JF
Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland.
Cotter
T G
TG
D000841:Anisomycin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D008564:Membrane Potentials; D008928:Mitochondria; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases