title: β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation.
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.
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Aejaz
authors.initials: A
authors.lastname: Sayeed
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Deming
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Duffy
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: McCue
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Translational Tumor Immunology Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gabrilovich
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rodeck
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, PA, USA.|Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy*; D000069473:Radiation Dose Hypofractionation; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
chemical_list: D000873:Anthracenes; D019012:Integrin beta1; C432165:pyrazolanthrone; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: FAK; TRAMP mice; insulin-like growth factor receptor; prostate cancer; β1 integrins