Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells.

Abstract

Notch signaling plays a critical role in the pathogenesis and progression of human malignancies but the precise role and mechanism of Notch-1 for tumor invasion remains unclear. In our earlier report, we showed that down-regulation of Notch-1 reduced nuclear factor-kappaB (NF-kappaB) DNA-binding activity and matrix metalloproteinase-9 (MMP-9) expression. Because NF-kappaB, VEGF, and MMPs are critically involved in the processes of tumor cell invasion and metastasis, we investigated the role and mechanism(s) by which Notch-1 down-regulation (using molecular approaches) may lead to the down-regulation of NF-kappaB, vascular endothelial growth factor (VEGF), and MMP-9, thereby inhibiting invasion of pancreatic cancer cells through Matrigel. We found that the down-regulation of Notch-1 by small interfering RNA decreased cell invasion, whereas Notch-1 overexpression by cDNA transfection led to increased tumor cell invasion. Consistent with these results, we found that the down-regulation of Notch-1 reduced NF-kappaB DNA-binding activity and VEGF expression. Down-regulation of Notch-1 also decreased not only MMP-9 mRNA and its protein expression but also inactivated the pro-MMP-9 protein to its active form. Taken together, we conclude that the down-regulation of Notch-1 could be an effective approach for the down-regulation and inactivation of NF-kappaB and its target genes, such as MMP-9 and VEGF expression, resulting in the inhibition of invasion and metastasis.

• Authors: Zhiwei Wang, Sanjeev Banerjee, Yiwei Li, K M Wahidur Rahman, Yuxiang Zhang, Fazlul H Sarkar
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 5 Pg. 2778-84 (Mar 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16510599 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)

Chemical References

• DNA, Complementary
• DNA, Neoplasm
• NF-kappa B
• NOTCH1 protein, human
• RNA, Small Interfering
• Receptor, Notch1
• Vascular Endothelial Growth Factor A
• Matrix Metalloproteinase 9

Topics

• DNA, Complementary (genetics)
• DNA, Neoplasm (metabolism)
• Down-Regulation
• Enzyme Activation
• Humans
• Matrix Metalloproteinase 9 (biosynthesis, genetics, metabolism)
• NF-kappa B (biosynthesis, genetics, metabolism)
• Neoplasm Invasiveness
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• RNA, Small Interfering (genetics)
• Receptor, Notch1 (biosynthesis, genetics, metabolism)
• Transcription, Genetic
• Transfection
• Vascular Endothelial Growth Factor A (biosynthesis, genetics)