Chemotherapy-induced interleukin-8 (IL-8) signaling reduces the sensitivity of 
prostate cancer cells to undergo apoptosis. In this study, we investigated how 
endogenous and drug-induced IL-8 signaling altered the extrinsic apoptosis 
pathway by determining the sensitivity of LNCaP and PC3 cells to administration 
of the death receptor agonist tumor necrosis factor-related apoptosis-inducing 
ligand (TRAIL). TRAIL induced concentration-dependent decreases in LNCaP and PC3 
cell viability, coincident with increased levels of apoptosis and the 
potentiation of IL-8 secretion. Administration of recombinant human IL-8 was 
shown to increase the mRNA transcript levels and expression of c-FLIP(L) and 
c-FLIP(S), two isoforms of the endogenous caspase-8 inhibitor. Pretreatment with 
the CXCR2 antagonist AZ10397767 significantly attenuated IL-8-induced c-FLIP 
mRNA up-regulation whereas inhibition of androgen receptor- and/or nuclear 
factor-kappaB-mediated transcription attenuated IL-8-induced c-FLIP expression 
in LNCaP and PC3 cells, respectively. Inhibition of c-FLIP expression was shown 
to induce spontaneous apoptosis in both cell lines and to sensitize these 
prostate cancer cells to treatment with TRAIL, oxaliplatin, and docetaxel. 
Coadministration of AZ10397767 also increased the sensitivity of PC3 cells to 
the apoptosis-inducing effects of recombinant TRAIL, most likely due to the 
ability of this antagonist to block TRAIL- and IL-8-induced up-regulation of 
c-FLIP in these cells. We conclude that endogenous and TRAIL-induced IL-8 
signaling can modulate the extrinsic apoptosis pathway in prostate cancer cells 
through direct transcriptional regulation of c-FLIP. Therefore, targeted 
inhibition of IL-8 signaling or c-FLIP expression in prostate cancer may be an 
attractive therapeutic strategy to sensitize this stage of disease to 
chemotherapy.