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

Authors

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

Publication/Presentation Date

8-16-2016

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.

Volume

7

Issue

33

First Page

52618

Last Page

52630

ISSN

1949-2553

Published In/Presented At

Sayeed, A., Lu, H., Liu, Q., Deming, D., 2nd, Duffy, A., McCue, P., Dicker, A. P., Davis, R. J., Gabrilovich, D., Rodeck, U., Altieri, D. C., & Languino, L. R. (2016). β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation. Oncotarget, 7(33), 52618–52630. https://doi.org/10.18632/oncotarget.10522

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

27438371

Department(s)

Administration and Leadership

Document Type

Article