A key antiapoptotic
transcription factor,
nuclear factor kappa-B (
NF-kappaB), is known to be critically important for
tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that
NF-kappaB transcription factor was constitutively activated in
androgen-independent prostate
carcinoma (PC) cell lines due to the upregulated activity of inhibitor of
NF-kappaB kinases (IKK). In this work, using
luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous kappaB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor,
PS1145, efficiently inhibited both basal and induced
NF-kappaB activity in PC cells. We found that
PS1145 induced
caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by
tumor necrosis factor alpha. We also showed that
PS1145 inhibited PC cell proliferation. Effects of
PS1145 on proliferation and apoptosis correlated with inhibition of
interleukin (IL)-6,
cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased
IL-6 protein level. In addition, we found that incubation with
PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting
NF-kappaB transcription factor to treat advanced PC.