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: Aejaz Sayeed, Huimin Lu, Qin Liu, David Deming 2nd, Alexander Duffy, Peter McCue, Adam P Dicker, Roger J Davis, Dmitry Gabrilovich, Ulrich Rodeck, Dario C Altieri, Lucia R Languino
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 33 Pg. 52618-52630 (Aug 16 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27438371 (Publication Type: Journal Article)

Chemical References

• Anthracenes
• Integrin beta1
• pyrazolanthrone
• Receptor, IGF Type 1
• Focal Adhesion Protein-Tyrosine Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• Adenocarcinoma (drug therapy, genetics, radiotherapy)
• Animals
• Anthracenes (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics, radiation effects)
• Combined Modality Therapy
• Focal Adhesion Protein-Tyrosine Kinases (genetics, metabolism)
• Gene Expression Profiling (methods)
• Humans
• Integrin beta1 (genetics, metabolism)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Mice, Transgenic
• Phosphorylation (drug effects, radiation effects)
• Prostatic Neoplasms (drug therapy, genetics, radiotherapy)
• Radiation Dose Hypofractionation
• Receptor, IGF Type 1 (genetics, metabolism)
• Tumor Burden (drug effects, genetics, radiation effects)