Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is one of the most promising anti-
cancer agents, but some
tumor types develop resistance to TRAIL. Here, we report that
chetomin, an inhibitor of
hypoxia-inducible factors, is a potent enhancer of TRAIL-induced apoptosis. TRAIL or
chetomin alone weakly induced apoptosis, but the combination of
chetomin and TRAIL synergistically induced apoptosis in
prostate cancer PC-3 cells. The combination of
chetomin and TRAIL induces the activation of
caspase-3, -8, -9 and -10. Among the apoptotic factors related to the TRAIL pathway,
chetomin markedly decreased the X-linked inhibitor of apoptosis (
XIAP) protein levels in a dose-dependent manner, but other IAP family members,
TRAIL receptors and Bcl-2 family members were not altered by
chetomin. Using XIAP
siRNA instead of
chetomin, down-regulation of XIAP sensitized PC-3 cells to TRAIL-induced apoptosis. Conversely, transient transfection of XIAP reduced the apoptotic response to combined treatment with
chetomin and TRAIL. Treatment with
chetomin induced a rapid decrease in
XIAP protein levels but had no effect on XIAP
mRNA levels. Since
chetomin-mediated XIAP down-regulation was completely prevented by
proteasome inhibitors, it was suggested that
chetomin induces the degradation of the
XIAP protein in a
proteasome-dependent manner. Additionally,
chetomin also sensitized
renal cancer Caki-1 cells and
bladder cancer UM-UC-3 cells to TRAIL-induced apoptosis via down-regulation of XIAP. Co-treatment of
chetomin and TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMC). Taken together, these findings suggest that TRAIL and
chetomin synergistically induce apoptosis in human
urogenital cancer cells through a mechanism that involves XIAP down-regulation by
chetomin.