UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network

Date

8-16-2016

Document Type

Article

Disciplines

Cancer Biology | Molecular Biology | Neoplasms | Oncology

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 (beta1wt /TRAMP) mice as well as in mice carrying a conditional ablation of beta1 integrins in the prostatic epithelium (beta1pc-/- /TRAMP). Since JNK is known to be suppressed by beta1 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 beta1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in beta1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of beta1wt /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 beta1/IGF-IR crosstalk and report that beta1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that beta1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.

Rights and Permissions

Citation: Oncotarget. 2016 Aug 16;7(33):52618-52630. doi: 10.18632/oncotarget.10522. Link to article on publisher's site. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.

DOI of Published Version

10.18632/oncotarget.10522

Related Resources

Link to Article in PubMed

Keywords

FAK, TRAMP mice, insulin-like growth factor receptor, prostate cancer, β1 integrins

Journal Title

Oncotarget

PubMed ID

27438371

Creative Commons License

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

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.