Priority Research Papers:
β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation
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Abstract
Aejaz Sayeed1,2, Huimin Lu1,2, Qin Liu1,3, David Deming II1,2, Alexander Duffy1,2, Peter McCue4, Adam P. Dicker5, Roger J. Davis6,7, Dmitry Gabrilovich1,8, Ulrich Rodeck5,9, Dario C. Altieri1,10 and Lucia R. Languino1,2,5
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 (β1wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1pc-/- /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 β1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1wt /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.
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