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Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity.

Publication ,  Journal Article
Wei, D; Wang, L; He, Y; Xiong, HQ; Abbruzzese, JL; Xie, K
Published in: Cancer Res
March 15, 2004

The aggressive biology of human pancreatic adenocarcinoma has been linked with overexpression of vascular endothelial growth factor (VEGF). Constitutive activation of the transcription factor Sp1 plays a critical role in VEGF overexpression. Recent studies indicated that celecoxib, a selective cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the underlying molecular mechanisms of this activity remain unclear. In the present study, we used a pancreatic cancer model to determine the role of Sp1 in the antitumor activity of celecoxib. Treatment of various pancreatic cancer cells with celecoxib suppressed VEGF expression at both the mRNA and protein level in a dose-dependent manner. VEGF promoter deletion and point mutation analyses indicated that a region between nucleotide -109 and -61 and its intact Sp1-binding sites were required for the inhibition of VEGF promoter activity by celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and transactivating activity. This decreased activity correlated with reduced Sp1 protein and its phosphorylation as determined using Western blot analysis. Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment inhibited tumor growth and metastasis. The antitumor activity was consistent with inhibition of angiogenesis as determined by evaluating tumor microvessel formation, which correlated with decreased Sp1 activity and VEGF expression. Collectively, our data provide a novel molecular mechanism for the antitumor activity of celecoxib and may help further improve its effectiveness in controlling pancreatic cancer growth and metastasis.

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Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

March 15, 2004

Volume

64

Issue

6

Start / End Page

2030 / 2038

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • Transcriptional Activation
  • Sulfonamides
  • Sp1 Transcription Factor
  • Response Elements
  • Pyrazoles
  • Promoter Regions, Genetic
  • Phosphorylation
  • Pancreatic Neoplasms
 

Citation

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Wei, D., Wang, L., He, Y., Xiong, H. Q., Abbruzzese, J. L., & Xie, K. (2004). Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res, 64(6), 2030–2038. https://doi.org/10.1158/0008-5472.can-03-1945
Wei, Daoyan, Liwei Wang, Yanjuan He, Henry Q. Xiong, James L. Abbruzzese, and Keping Xie. “Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity.Cancer Res 64, no. 6 (March 15, 2004): 2030–38. https://doi.org/10.1158/0008-5472.can-03-1945.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

March 15, 2004

Volume

64

Issue

6

Start / End Page

2030 / 2038

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tumor Cells, Cultured
  • Transcriptional Activation
  • Sulfonamides
  • Sp1 Transcription Factor
  • Response Elements
  • Pyrazoles
  • Promoter Regions, Genetic
  • Phosphorylation
  • Pancreatic Neoplasms