β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation

// Aejaz Sayeed 1,2 , Huimin Lu 1,2 , Qin Liu 1,3 , David Deming II 1,2 , Alexander Duffy 1,2 , Peter McCue 4 , Adam P. Dicker 5 , Roger J. Davis 6,7 , Dmitry Gabrilovich 1,8 , Ulrich Rodeck 5,9 , Dario C. Altieri 1,10 and Lucia R. Languino 1,2,5 1 Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA 2 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA 3 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA 4 Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA 5 Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA 6 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA 7 Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA 8 Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, PA, USA 9 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA 10 Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA Correspondence to: Lucia R. Languino, email: // Keywords : TRAMP mice, prostate cancer, β1 integrins, FAK, insulin-like growth factor receptor Received : November 25, 2015 Accepted : June 15, 2016 Published : July 11, 2016 Abstract Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (β1 wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1 pc-/- /TRAMP). Since JNK is known to be suppressed by β1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in β1 pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1 pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1 wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the β1/IGF-IR crosstalk and report that β1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that β1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.