Inhibition of IkappaB kinase beta restrains oncogenic proliferation of pancreatic cancer cells.
OBJECTIVE
Pancreatic cancer is characterized by an extremely poor prognosis due to the aggressive disease course and lack of effective therapeutic intervention. IkappaB kinase (IKK), a central kinase for nuclear factor-kappaB (NF-kappaB) activation, is often constitutively activated in pancreatic cancer cells, playing a crucial role in the malignant phenotype and resistance to anti-cancer agents. This study explored how specific inhibition of IKKbeta suppresses oncogenic proliferation of pancreatic cancer cells.


METHODS
We employed two different approaches, RNA interference-mediated depletion of IKKbeta (IKKbetai) and use of a novel molecularly designed IKKbeta inhibitor IMD-0354 to investigate the effects on the in vitro and in vivo growth and apoptotic response of pancreatic cancer cells.


RESULTS
IKKbetai and IMD-0354 efficiently suppressed constitutive NF-kappaB activity and the growth of pancreatic cancer cells in monolayer and soft agar. IMD-0354 induced Annexin V expression, a typical apoptotic cell response. Notably, daily administration of IMD-0354 significantly suppressed tumor growth in NOD/SCID/gamma c(null) (NOG) mice without any deleterious side effect.


CONCLUSIONS
These results identify IKKbeta as an attractive molecular target for pancreatic cancer therapy.
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University Tokyo, Japan.
Takanori
T
Ochiai
Yasunori
Y
Saito
Tatsuya
T
Saitoh
M Zahidunnabi
MZ
Dewan
Ayumi
A
Shioya
Maki
M
Kobayashi
Hiroshi
H
Kawachi
Susumu
S
Muto
Akiko
A
Itai
Shin
S
Uota
Yoshinobu
Y
Eishi
Naoki
N
Yamamoto
Shinji
S
Tanaka
Shigeki
S
Arii
Shoji
S
Yamaoka
D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
D001549:Benzamides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D051550:I-kappa B Kinase