Inhibition of IkappaB kinase beta restrains oncogenic proliferation of pancreatic cancer cells.

Purpose: Pancreatic cancer is characterized by an extremely poor prognosis due to the aggressive disease course and lack of effective therapeutic intervention. IOB kinase (IKK), a central kinase for nuclear factor-OB (NF-OB) 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 IKKC suppresses oncogenic proliferation of pancreatic cancer cells. Experimental Design: We employed two different approaches, RNA interference-mediated depletion of IKKC (IKKCi) and use of a novel molecularly designed IKKC inhibitor IMD-0354 to investigate the effects on the in vitro and in vivo growth and apoptotic response of pancreatic cancer cells. Results: IKKCi and IMD-0354 efficiently suppressed constitutive NF-OB 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/Ic null (NOG) mice without any deleterious side effect. Conclusions: These results identify IKKC as an attractive molecular target for pancreatic cancer therapy.