Previously, we reported that inhibition of
arachidonate 5-lipoxygenase triggers massive apoptosis in both
androgen-sensitive (LNCaP) and
androgen-refractory (PC3) human
prostate cancer cells within hours of treatment [Proc. Natl. Acad. Sci. USA 95 (1998) 13182-13187]. Apoptosis was prevented by exogenous 5(S)-HETE, a product of
5-lipoxygenase, indicating a role of this
eicosanoid as an essential survival/anti-apoptotic factor for
prostate cancer cells. However, nothing was clearly known about details of the underlying molecular mechanisms or events mediating the induction of fulminating apoptosis in these cells. This report documents the fact that inhibition of
arachidonate 5-lipoxygenase induces rapid activation of
c-Jun N-terminal kinase (JNK) in human
prostate cancer cells which is prevented by the
5-lipoxygenase metabolite, 5(S)-HETE. Activation of JNK is unaffected by the cell-permeable tetra-
peptide inhibitors of
caspase 8 or
caspase 3 (
IETD-FMK and DEVD-FMK), though these inhibitors effectively blocked apoptosis triggering, suggesting that activation of JNK is independent or upstream of
caspase activation. Both
5-lipoxygenase inhibition-induced activation of JNK and induction of apoptosis are prevented by
curcumin, an inhibitor of JNK-signaling pathway. Apoptosis is also blocked by
SP600125, a specific inhibitor of JNK activity, indicating that JNK activity is required for the induction of apoptosis in these cells. These findings suggest that the metabolites of
arachidonate 5-lipoxygenase promote survival of
prostate cancer cells involving down-regulation of stress-activated
protein kinase.