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, Aejaz; Lu, Huimin; Liu, Qin; Deming Ii, David; Duffy, Alexander; McCue, Peter; Dicker, Adam P.; Davis, Roger J.; Gabrilovich, Dmitry; Rodeck, Ulrich; Altieri, Dario C.; and Languino, Lucia R., "beta1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation" (2016). Open Access Articles. 2794.
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This work is licensed under a Creative Commons Attribution 3.0 License.