Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer.
The transcription factor NF-kappaB/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-kappaB/Rel-binding activity consists of NF-kappaB1(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 PI3 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 Panc1 cells. Our data demonstrate that an EGF-R/Ras/PI3 kinase/Akt/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.
Liptay
Susanne
S
Department of Pediatrics, University of Ulm, Ulm, Germany.
Weber
Christoph K
CK
Ludwig
Leopold
L
Wagner
Martin
M
Adler
Guido
G
Schmid
Roland M
RM
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D002455:Cell Division; D002467:Cell Nucleus / Q000737:chemistry; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D052002:NF-kappa B p50 Subunit; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D018631:ras Proteins