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

Olivier De Wever UGent, Joëlle Sobczak-Thépot, Anne-Sophie Vercoutter-Edouart, Jean-Claude Michalski, Radia Ouelaa-Benslama, Dwayne G Stupack, Marc Bracke UGent, Jean YJ Wang, christian Gespach and Shahin Emami (2011) INTERNATIONAL JOURNAL OF ONCOLOGY. 39(2). p.393-400
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 alpha 5 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 alpha 5 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 (gamma-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 gamma-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 subunit, DNA-PK-cs) and SP600125 (JNK2, stress activated protein kinase/c-Jun N-terminal kinase-2). Adhesion to FN also potentiated the gamma-H2AX signals and the cytotoxic effects of cisplatin in human colon tumor-derived myofibroblasts. These data provide evidence that FN promotes DNA damage recognition and chemosensitization to cisplatin via the potentiation of the DNA damage signaling responses in human colon cancer cells and tumor-derived myofibroblasts.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
PHOSPHORYLATION, EXPRESSION, PROGRESSION, ACTIVATION, cisplatin, gamma-H2AX, phosphatidyl inositol-3-kinase-related protein kinases, ataxia telangiectasia mutated, check-point kinase 2, c-Jun-NH2-terminal kinase-2, p53, alpha 5-integrins, cell cycle, human colon tumor myofibroblasts, DOUBLE-STRAND BREAKS, HISTONE H2AX, EXTRACELLULAR-MATRIX, MAMMALIAN-CELLS, INTEGRIN, ATM
journal title
INTERNATIONAL JOURNAL OF ONCOLOGY
Int. J. Oncol.
volume
39
issue
2
pages
393 - 400
Web of Science type
Article
Web of Science id
000292623700011
JCR category
ONCOLOGY
JCR impact factor
2.399 (2011)
JCR rank
108/190 (2011)
JCR quartile
3 (2011)
ISSN
1019-6439
DOI
10.3892/ijo.2011.1034
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2941442
handle
http://hdl.handle.net/1854/LU-2941442
date created
2012-06-28 13:25:16
date last changed
2012-07-10 13:52:19
@article{2941442,
  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 alpha 5 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 alpha 5 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 (gamma-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 gamma-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 subunit, DNA-PK-cs) and SP600125 (JNK2, stress activated protein kinase/c-Jun N-terminal kinase-2). Adhesion to FN also potentiated the gamma-H2AX signals and the cytotoxic effects of cisplatin in human colon tumor-derived myofibroblasts. These data provide evidence that FN promotes DNA damage recognition and chemosensitization to cisplatin via the potentiation of the DNA damage signaling responses in human colon cancer cells and tumor-derived myofibroblasts.},
  author       = {De Wever, Olivier and Sobczak-Th{\'e}pot, Jo{\"e}lle and Vercoutter-Edouart, Anne-Sophie and Michalski, Jean-Claude and Ouelaa-Benslama, Radia and Stupack, Dwayne G and Bracke, Marc and Wang, Jean YJ and Gespach, christian and Emami, Shahin},
  issn         = {1019-6439},
  journal      = {INTERNATIONAL JOURNAL OF ONCOLOGY},
  keyword      = {PHOSPHORYLATION,EXPRESSION,PROGRESSION,ACTIVATION,cisplatin,gamma-H2AX,phosphatidyl inositol-3-kinase-related protein kinases,ataxia telangiectasia mutated,check-point kinase 2,c-Jun-NH2-terminal kinase-2,p53,alpha 5-integrins,cell cycle,human colon tumor myofibroblasts,DOUBLE-STRAND BREAKS,HISTONE H2AX,EXTRACELLULAR-MATRIX,MAMMALIAN-CELLS,INTEGRIN,ATM},
  language     = {eng},
  number       = {2},
  pages        = {393--400},
  title        = {Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts},
  url          = {http://dx.doi.org/10.3892/ijo.2011.1034},
  volume       = {39},
  year         = {2011},
}

Chicago
De Wever, Olivier, Joëlle Sobczak-Thépot, Anne-Sophie Vercoutter-Edouart, Jean-Claude Michalski, Radia Ouelaa-Benslama, Dwayne G Stupack, Marc Bracke, Jean YJ Wang, christian Gespach, and Shahin Emami. 2011. “Priming and Potentiation of DNA Damage Response by Fibronectin in Human Colon Cancer Cells and Tumor-derived Myofibroblasts.” International Journal of Oncology 39 (2): 393–400.
APA
De Wever, O., Sobczak-Thépot, J., Vercoutter-Edouart, A.-S., Michalski, J.-C., Ouelaa-Benslama, R., Stupack, D. G., Bracke, M., et al. (2011). Priming and potentiation of DNA damage response by fibronectin in human colon cancer cells and tumor-derived myofibroblasts. INTERNATIONAL JOURNAL OF ONCOLOGY, 39(2), 393–400.
Vancouver
1.
De Wever O, Sobczak-Thépot J, Vercoutter-Edouart A-S, Michalski J-C, Ouelaa-Benslama R, Stupack DG, 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;39(2):393–400.
MLA
De Wever, Olivier, Joëlle Sobczak-Thépot, Anne-Sophie Vercoutter-Edouart, et al. “Priming and Potentiation of DNA Damage Response by Fibronectin in Human Colon Cancer Cells and Tumor-derived Myofibroblasts.” INTERNATIONAL JOURNAL OF ONCOLOGY 39.2 (2011): 393–400. Print.