Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-kappaB signaling pathway with the anti-epidermal growth factor antibody IMC-C225.
We have previously demonstrated that RelA is constitutively activated in the majority of human pancreatic cancers and plays an important role in tumorigenesis and metastasis. The antiapoptotic gene bcl-xl is a downstream target of RelA, and regulation of bcl-xl transcription is mediated directly by the nuclear factor kappaB (NF-kappaB) binding sites present in the upstream promoter element of the bcl-xl gene. In this study we investigated the effects of inhibition of epidermal growth factor receptor (EGFR) signaling pathway with the anti-EGFR monoclonal antibody IMC-C225 on constitutive NF-kappaB activation and regulation of apoptosis-related genes in human pancreatic cancer cells. We found that activation of EGFR can be blocked with the anti-EGFR antibody IMC-C225 in the human pancreatic cancer cell line MDA Panc-28, leading to a marked decrease in constitutive NF-kappaB DNA binding activity. Our data also suggest that downregulation of NF-kappaB DNA binding activity by IMC-C225 leads to a decrease in bcl-xl and bfl-1 expression. Therefore, targeting the NF-kappaB signaling pathway with an anti-EGFR antibody may be one strategy to restore apoptosis in human pancreatic cancer cells, thereby enhancing the effect of chemotherapy and radiation therapy.
Sclabas
Guido M
GM
Department of Surgical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
Fujioka
Shuichi
S
Schmidt
Christian
C
Fan
Zhen
Z
Evans
Douglas B
DB
Chiao
Paul J
PJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002455:Cell Division; D000068818:Cetuximab; D004247:DNA / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D003841:Deoxycytidine; D004247:DNA; D066246:ErbB Receptors; D000068818:Cetuximab; D000093542:Gemcitabine