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

Authors

Aejaz Sayeed, Prostate Cancer Discovery and Development ProgramFollow
Huimin Lu, Prostate Cancer Discovery and Development Program; Thomas Jefferson University, PhiladelphiaFollow
Qin Liu, Prostate Cancer Discovery and Development Program; The Wistar InstituteFollow
David Deming, Prostate Cancer Discovery and Development Program; Thomas Jefferson University, PhiladelphiaFollow
Alexander Duffy, Prostate Cancer Discovery and Development Program; Thomas Jefferson University, PhiladelphiaFollow
Peter McCue, Thomas Jefferson UniversityFollow
Adam P. Dicker, Thomas Jefferson UniversityFollow
Roger J. Davis, University of Massachusetts Medical School
Dmitry Gabrilovich, Prostate Cancer Discovery and Development Program; The Wistar Institute
Ulrich Rodeck, Thomas Jefferson UniversityFollow
Dario C. Altieri, Prostate Cancer Discovery and Development Program; The Wistar InstituteFollow
Lucia R. Languino, Thomas Jefferson University; Prostate Cancer Discovery and Development ProgramFollow

Document Type

Article

Publication Date

8-1-2016

Comments

This article has been peer reviewed. It is the author’s final published version in Oncotarget

Volume 7, Issue 33, August 2016, Pages 52618-52630.

The published version is available at 10.18632/oncotarget.10522. Copyright © Sayeed et al.

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.

Recommended Citation

Sayeed, Aejaz; Lu, Huimin; Liu, Qin; Deming, David; Duffy, Alexander; McCue, Peter; Dicker, Adam P.; Davis, Roger J.; Gabrilovich, Dmitry; Rodeck, Ulrich; Altieri, Dario C.; and Languino, Lucia R., "β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation." (2016). Department of Cancer Biology Faculty Papers. Paper 97.
https://jdc.jefferson.edu/cbfp/97

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

PubMed ID

27438371