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

Aejaz Sayeed,Dario C Altieri,Lucia R Languino,Alexander Duffy,David Deming Ii,Adam P Dicker,Peter Mccue,Dmitry Gabrilovich,Ulrich Rodeck,Roger J Davis,Huimin Lu,Qin Liu

doi:10.18632/oncotarget.10522

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.

Highlights

Integrin-mediated adhesion of cancer cells to the extracellular matrix regulates the cellular response to ionizing radiation [1,2,3]
To assess the importance of Jun NH2-terminal kinase (JNK) activation in response to radiation, 20 week-old β1pc-/- /transgenic adenocarcinoma of mouse prostate (TRAMP) mice were treated with hypofractionated radiation regimen that consisted of 10 Gy fractions for 5 consecutive days
Using a novel hypofractionated radiation schedule that effectively blocks prostate tumor growth in TRAMP mice, we show that blocking JNK signaling using a JNK1, 2 and 3 inhibitor (SP600125), counteracts the effects of therapeutic radiation and leads to tumor growth and progression, in a β1 integrin-dependent manner

Summary

Introduction

Integrin-mediated adhesion of cancer cells to the extracellular matrix regulates the cellular response to ionizing radiation [1,2,3]. In the current study, we have investigated the effect of hypofractionated high dose radiation administered at shorter intervals (mice are irradiated with a total dose of 50 Gy, carried out in fractionated doses of 10 Gy, consecutively for 5 days). This simulates the approach proposed for clinical use in an effort to alleviate patient inconvenience and reduce health care costs (Reviewed in [9]). An improved understanding of the mechanisms involved in radiation-induced tumor regression may provide novel strategies of intervention in the treatment of human malignancies

Methods

Results

Conclusion