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Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model.

Publication ,  Journal Article
Trevino, JG; Summy, JM; Lesslie, DP; Parikh, NU; Hong, DS; Lee, FY; Donato, NJ; Abbruzzese, JL; Baker, CH; Gallick, GE
Published in: Am J Pathol
March 2006

The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable expression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Src expression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, and proliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activated protein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005). On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged; however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis was significantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine this possibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selective inhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases was significantly reduced in treated mice compared with controls. These results demonstrate that Src activation contributes to pancreatic tumor progression in this model, offering Src as a candidate for targeted therapy.

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Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

March 2006

Volume

168

Issue

3

Start / End Page

962 / 972

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Vascular Endothelial Growth Factor A
  • Thiazoles
  • RNA, Small Interfering
  • Pyrimidines
  • Proto-Oncogene Proteins pp60(c-src)
  • Proto-Oncogene Proteins c-yes
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Phosphorylation
 

Citation

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Trevino, J. G., Summy, J. M., Lesslie, D. P., Parikh, N. U., Hong, D. S., Lee, F. Y., … Gallick, G. E. (2006). Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol, 168(3), 962–972. https://doi.org/10.2353/ajpath.2006.050570
Trevino, Jose G., Justin M. Summy, Donald P. Lesslie, Nila U. Parikh, David S. Hong, Francis Y. Lee, Nicholas J. Donato, James L. Abbruzzese, Cheryl H. Baker, and Gary E. Gallick. “Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model.Am J Pathol 168, no. 3 (March 2006): 962–72. https://doi.org/10.2353/ajpath.2006.050570.
Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, et al. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol. 2006 Mar;168(3):962–72.
Trevino, Jose G., et al. “Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model.Am J Pathol, vol. 168, no. 3, Mar. 2006, pp. 962–72. Pubmed, doi:10.2353/ajpath.2006.050570.
Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, Donato NJ, Abbruzzese JL, Baker CH, Gallick GE. Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol. 2006 Mar;168(3):962–972.
Journal cover image

Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

March 2006

Volume

168

Issue

3

Start / End Page

962 / 972

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Vascular Endothelial Growth Factor A
  • Thiazoles
  • RNA, Small Interfering
  • Pyrimidines
  • Proto-Oncogene Proteins pp60(c-src)
  • Proto-Oncogene Proteins c-yes
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Phosphorylation