The
tumor necrosis factor (
TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in
prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to
therapy. Although inhibition of TNF signaling by pharmacological agents or
monoclonal antibodies has gained importance in the field of
cancer therapy, toxicity to normal cells has impaired their extensive use for
cancer treatment. We previously identified a natural, nontoxic compound
psoralidin that inhibited viability and induced apoptosis in
androgen independent
prostate cancer (
AIPC) cells. Thus, the goal of our study is to investigate whether
psoralidin inhibits TNF-mediated prosurvival signaling in
AIPC cells. Our results suggest that
psoralidin inhibits constitutive and TNF-induced expression of
TNF-alpha and its downstream prosurvival signaling molecules such as
NF-kappaB and Bcl-2 in
AIPC cells. On the other hand,
psoralidin simultaneously induces the
death receptor (DR)-mediated apoptotic signaling eventually causing the activation of
caspase cascade and resultant induction of apoptosis.
Oral administration of
psoralidin inhibits expression of
TNF-alpha and
NF-kappaB/p65 in
tumor sections, resulting in
tumor regression in PC-3 xenografts. Our results suggest that
psoralidin inhibits TNF-mediated survival signaling in
AIPC and thus is a potent therapeutic agent for
prostate cancer.