1. Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.
- Author
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Patel R, Cooper DE, Kadakia KT, Allen A, Duan L, Luo L, Williams NT, Liu X, Locasale JW, and Kirsch DG
- Subjects
- Animals, Mice, Glucose metabolism, Disease Models, Animal, Radiation Tolerance, Glutamine metabolism, Glutaminase metabolism, Glutaminase genetics, Glutaminase antagonists & inhibitors, Sarcoma metabolism, Sarcoma radiotherapy, Sarcoma genetics
- Abstract
Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7
Cre-ER-T2/+ ; NrasLSL-G12D/+ ; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse13 C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS., (© 2024. The Author(s).)- Published
- 2024
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