Effects of IKK inhibitor PS1145 on NF-kappaB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells.
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.
Yemelyanov
A
A
Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Gasparian
A
A
Lindholm
P
P
Dang
L
L
Pierce
J W
JW
Kisseljov
F
F
Karseladze
A
A
Budunova
I
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D011725:Pyridines; D051550:I-kappa B Kinase