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Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.

Publication ,  Journal Article
Wang, Z; Kong, D; Banerjee, S; Li, Y; Adsay, NV; Abbruzzese, J; Sarkar, FH
Published in: Cancer Res
December 1, 2007

Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-kappaB (NF-kappaB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-kappaB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-kappaB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA-transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-kappaB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 1, 2007

Volume

67

Issue

23

Start / End Page

11377 / 11385

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Umbilical Veins
  • Transfection
  • Transcription, Genetic
  • Signal Transduction
  • Receptor, Notch1
  • RNA, Small Interfering
  • Platelet-Derived Growth Factor
  • Pancreatitis, Chronic
  • Pancreatic Neoplasms
 

Citation

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MLA
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Wang, Z., Kong, D., Banerjee, S., Li, Y., Adsay, N. V., Abbruzzese, J., & Sarkar, F. H. (2007). Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling. Cancer Res, 67(23), 11377–11385. https://doi.org/10.1158/0008-5472.CAN-07-2803
Wang, Zhiwei, Dejuan Kong, Sanjeev Banerjee, Yiwei Li, N Volkan Adsay, James Abbruzzese, and Fazlul H. Sarkar. “Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.Cancer Res 67, no. 23 (December 1, 2007): 11377–85. https://doi.org/10.1158/0008-5472.CAN-07-2803.
Wang Z, Kong D, Banerjee S, Li Y, Adsay NV, Abbruzzese J, et al. Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling. Cancer Res. 2007 Dec 1;67(23):11377–85.
Wang, Zhiwei, et al. “Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.Cancer Res, vol. 67, no. 23, Dec. 2007, pp. 11377–85. Pubmed, doi:10.1158/0008-5472.CAN-07-2803.
Wang Z, Kong D, Banerjee S, Li Y, Adsay NV, Abbruzzese J, Sarkar FH. Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling. Cancer Res. 2007 Dec 1;67(23):11377–11385.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

December 1, 2007

Volume

67

Issue

23

Start / End Page

11377 / 11385

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Umbilical Veins
  • Transfection
  • Transcription, Genetic
  • Signal Transduction
  • Receptor, Notch1
  • RNA, Small Interfering
  • Platelet-Derived Growth Factor
  • Pancreatitis, Chronic
  • Pancreatic Neoplasms