Program in Molecular Medicine; UMass Metabolic Network
Cancer Biology | Molecular Biology | Neoplasms | Oncology
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.
FAK, TRAMP mice, insulin-like growth factor receptor, prostate cancer, β1 integrins
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DOI of Published Version
Oncotarget. 2016 Aug 16;7(33):52618-52630. doi: 10.18632/oncotarget.10522. Link to article on publisher's site
Sayeed A, Lu H, Liu Q, Deming Ii D, Duffy A, McCue P, Dicker AP, Davis RJ, Gabrilovich D, Rodeck U, Altieri DC, Languino LR. (2016). beta1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation. Open Access Articles. https://doi.org/10.18632/oncotarget.10522. Retrieved from https://escholarship.umassmed.edu/oapubs/2794
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This work is licensed under a Creative Commons Attribution 3.0 License.