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 1

β1 Integrin inhibition reduces HNSCC cell survival and confers radiosensitization in vitro and tumor growth delay in vivo.

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β1 Integrin inhibition reduces HNSCC cell survival and confers radiosens...
(A) Western blot analysis of β1 integrin in HNSCC cell lines. β-Actin served as loading control. (B) Work flow of colony forming assay upon monoclonal inhibitory anti–β1 integrin antibody (AIIB2) treatment of 3D lrECM cell cultures alone or combined with x-rays. (C) Clonogenic survival of 3D cell cultures upon AIIB2 administration (nonspecific IgG#1 as control) (mean ± SD; n = 3; t test; **P < 0.01). conc., concentration. (D) Clonogenic radiation survival (0–6 Gy; mean ± SD; n = 3; t test; *P < 0.05, **P < 0.01) of 1-hour AIIB2 pretreated 3D lrECM cell cultures (nonspecific IgG#1 as control). (E) Experimental in vivo setup. Subcutaneous UTSCC15 tumors were grown in immunocompromised mice to a diameter of 6 mm. Mice received 3 antibody injections (day 0, 3, 6). Where indicated, 20 Gy x-ray radiation was applied 4 hours after second antibody injection. ∅, diameter. (F) Time to reach 2-fold and 5-fold tumor starting volume upon AIIB2 (or IgG#2 control) treatment is plotted against irradiation (medians ± 95% CI; n = 10–18; Mann-Whitney U test). Dashed lines separate IgG#2 control data from data of AIIB2 treatment. *P < 0.05, **P < 0.01. See also Supplemental Figures 1–11.