Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer.
The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-kappaB (NF-kappaB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-kappaB and down-regulation of NF-kappaB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that down-regulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-kappaB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer.
Wang
Zhiwei
Z
Departments of Pathology and Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University, 110 East Warren Avenue, Detroit, MI 48201, USA.
Sengupta
Radha
R
Banerjee
Sanjeev
S
Li
Yiwei
Y
Zhang
Yuxiang
Y
Rahman
K M Wahidur
KM
Aboukameel
Amro
A
Mohammad
Ramzi
R
Majumdar
Adhip P N
AP
Abbruzzese
James L
JL
Sarkar
Fazlul H
FH
D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D006023:Glycoproteins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; C512478:EGFR protein, human; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9