Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts - Sorbonne Université Access content directly
Journal Articles International Journal of Oncology Year : 2011

Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts

Wever Olivier De
  • Function : Author
Vercoutter-Edouart Anne-Sophie
  • Function : Author
Michalski Jean-Claude
  • Function : Author
Ouelaa-Benslama Radia
  • Function : Author
Stupack Dwayne G.
  • Function : Author
Wang Jean Y.J.
  • Function : Author
Shahin Emami
  • Function : Author
  • PersonId : 1239809
Gespach Christian
  • Function : Author
Bracke Marc
  • Function : Author

Abstract

We have previously shown that the genotoxin-induced apoptosis in mouse embryo fibroblasts was enhanced by the extracellular matrix protein fibronectin (FN). In the present study, we tested the hypothesis that FN regulates the DNA damage response (DDR) signaling pathways in HCT116 (p53-wt) and HT29 (p53-mut) human colon cancer cells and tumor-derived myofibroblasts. DNA damage recognition mechanisms were analyzed by immunofluorescence staining, cell cycle analysis and immunoblotting addressed at specific molecular sensors and executors involved in the DDR pathways. The results show that FN, but not collagen type IV or Matrigel, initiates and potentiates the DDR to the anticancer drug cisplatin in an α5 integrin and cell cycle-dependent manner (S and G2/M phases) in human colon cancer cells. Accordingly, we demonstrate that adhesion of HCT116 cells to FN upregulated the expression of α5 integrin FN receptors at the cell surface. These FN-induced DDR pathways include the concerted phosphorylation of histone H2AX on Ser 139 detected as nuclear foci (γ-H2AX, 15 and 25 kDa forms), of ataxia telangiectasia mutated (ATM-Ser 1981), checkpoint kinase 2 (CHK2-Thr 68 , 62 and 67 kDa) and p53-Ser 15. These FN-induced γ-H2AX signals were interrupted or attenuated by selective inhibitors acting on the DDR pathway kinases, including wortmannin (targeting the phosphatidylinositol-3-kinase-related protein kinases, PIKK), KU55933 (ATM), NU7026 (DNA-dependent protein kinase catalytic
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Dates and versions

hal-04040770 , version 1 (22-03-2023)

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Wever Olivier De, Joëlle Sobczak-Thepot, Vercoutter-Edouart Anne-Sophie, Michalski Jean-Claude, Ouelaa-Benslama Radia, et al.. Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts. International Journal of Oncology, 2011, ⟨10.3892/ijo.2011.1034⟩. ⟨hal-04040770⟩
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