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

present in the nucleus in primary human pancreatic cancer samples as well as in pancreatic cancer cell lines. NF-kappaB/Rel-binding activity consists of NF-kappaBI (p50) and RelA(p65). Constitutive NF-kappaB/Rel activity correlates with IkappaB kinase (IKK) activity and can be blocked by dominant negative mutants of IKKbeta and to a lesser extent by IKKalpha. Constitutive NF-kappaB/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-kappaB-dependent transcription. Inhibition of constitutive IKK or NF-kappaB/Rel activity increased the number of apoptotic cells. Stably expressing a nondegradable form of IkappaBalpha inhibited anchorage-dependent and independent proliferation in MiaPaCa2 and Pancl cells. Our data demonstrate that an EGF-R/Ras/P13 Icinase/Alt/IKK-dependent pathway contributes to constitutive NF-kappaB/Rel activity in pancreatic cancer. Inhibition of NF-kappaB/Rel activity reveals a mitogenic and antiapoptotic role for NF-kappaB/Rel in pancreatic cancer. (C) 2003 Wiley-Liss, Inc.