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β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy
Iris Eke, … , Veit Sandfort, Nils Cordes
Iris Eke, … , Veit Sandfort, Nils Cordes
Published March 1, 2012
Citation Information: J Clin Invest. 2012;122(4):1529-1540. https://doi.org/10.1172/JCI61350.
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Research Article Oncology Article has an altmetric score of 2

β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy

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Abstract

Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of β1 integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenografted mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of β1 integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregulated JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of β1 integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy.

Authors

Iris Eke, Yvonne Deuse, Stephanie Hehlgans, Kristin Gurtner, Mechthild Krause, Michael Baumann, Anna Shevchenko, Veit Sandfort, Nils Cordes

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Figure 4

Disassembly of FAK/cortactin interaction upon β1 integrin inhibition.

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Disassembly of FAK/cortactin interaction upon β1 integrin inhibition.
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(A) Phase-contrast microscopy for cell rounding (arrows) upon AIIB2-mediated β1 integrin inhibition (IgG#1 as control). Scale bar: 10 μm. (B) Time course Western blot analysis on protein lysates from AIIB2-treated 3D cell cultures (n = 3). β-Actin served as loading control. Ezr/Rad/Moes, ezrin/radixin/moesin. (C) PLA using anti–β1 integrin FAK and anti-CTTN antibodies and confocal microscopy on AIIB2-treated cells. DAPI was used for nuclear staining. Scale bar: 10 μm. (D) Western blot analysis of FAK and CTTN expression and phosphorylation of FAK immunoprecipitates. FAK immunoprecipitation was done from whole cell lysates of cells treated with AIIB2 or TS2/16 (a β1 integrin–stimulating antibody). IgG#1 and IgG#3 served as controls. Results show mean ± SD (n = 3; t test; **P < 0.01). Rel, relative; coprecipitation, coimmunoprecipitation. (E) Western blot analysis of FAK and CTTN expression and phosphorylation of GFP immunoprecipitates. GFP immunoprecipitation was done from whole cell lysates of AIIB2-treated FAKca-GFP, FAKwt-GFP, and GFP transfectants. IgG#1 served as control. Data show mean ± SD (n = 3; t test; **P < 0.01). See also Supplemental Figures 16–19.

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