Mitogenic and antiapoptotic role of constitutive NF-κB/Rel activity in pancreatic cancer

Abstract

The transcription factor NF-κB/Rel was found to be constitutively activated in human pancreatic cancer. RelA is present in the nucleus in primary human pancreatic cancer samples as well as in pancreatic cancer cell lines. NF-κB/Rel-binding activity consists of NF-κB1 (p50) and RelA(p65). Constitutive NF-κB/Rel activity correlates with IκB kinase (IKK) activity and can be blocked by dominant negative mutants of IKKβ and to a lesser extent by IKKα. Constitutive NF-κB/Rel activity and the transactivation potential of RelA(p65) can be inhibited by dominant negative mutant Ras, the P13 kinase inhibitor LY294002, or dominant negative mutant Akt kinase. Transfection of a dominant negative mutant epidermal growth factor receptor (EGF-R), EGF-R kinase inhibitor Tyrphostin and LY 294002 blocked IKK activity and NF-κB-dependent transcription. Inhibition of constitutive IKK or NF-κB/Rel activity increased the number of apoptotic cells. Stably expressing a nondegradable form of IκBα inhibited anchorage-dependent and -independent proliferation in MiaPaCa2 and Panc1 cells. Our data demonstrate that an EGF-R/Ras/P13 kinase/Akt/IKK-dependent pathway contributes to constitutive NF-κB/Rel activity in pancreatic cancer. Inhibition of NF-κB/Rel activity reveals a mitogenic and antiapoptotic role for NF-κB/Rel in pancreatic cancer. © 2003 Wiley-Liss, Inc.