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

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

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 2

Perturbed FAK/JNK1 signaling by β1 integrin inhibition causes tumor cell radiosensitization.

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Perturbed FAK/JNK1 signaling by β1 integrin inhibition causes tumor cell...
(A) Phosphoproteome array-based analysis on whole cell lysates of 3D UTSCC15 cell cultures treated for 1 hour with AIIB2 (IgG#1 as control) is plotted as fold change after normalization to total protein expression (complete list in Supplemental Table 3). (B) Western blotting on protein lysates from AIIB2-treated 3D cell cultures and UTSCC15 tumor xenografts (n = 3). Numbers indicate animal numbers. (C) PLA using anti–β1 integrin and anti–FAK Y397 antibodies and confocal microscopy on AIIB2-treated (100 μg/ml; 1 hour) cells (IgG#1 as control). DAPI was used for nuclear staining. Scale bar: 10 μm. (D) Clonogenic radiation survival of FAK or JNK1 or FAK/JNK1 double knockdown. Data show mean ± SD (n = 3; t test; *P < 0.05, **P < 0.01). Co, nonspecific siRNA control. (E) Clonogenic radiation survival of FAK or JNK1 depleted cells, with or without AIIB2 treatment (100 μg/ml, 1 hour) and irradiation with 2 Gy (mean ± SD; n = 3; t test; **P < 0.01). See also Supplemental Figures 1–14.