RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向谷氨酰胺代谢可改善体内肉瘤对放射治疗的反应
英文原题：Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.
查看英文原题
Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.
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中文摘要
多种肿瘤代谢表型受环境和遗传损伤的影响。这些表型是否延伸至横纹肌肉瘤（RMS），以及如何利用这些表型设计新的治疗方法，仍是一个未解的问题。
因此，我们利用了一种 Pax7 Cre-ER-T2/+ ; Nras LSL-G12D/+ ; p53 fl/fl (P7NP) 小鼠肉瘤模型，该模型携带的突变最常见于人类胚胎型 RMS。为了研究代谢，我们向患有肉瘤的小鼠输注 13 C 标记的葡萄糖或谷氨酰胺，结果显示肉瘤比健康肌肉组织消耗更多的葡萄糖和谷氨酰胺。
然而，我们揭示在放射治疗（RT）后，代谢从葡萄糖消耗显著转向谷氨酰胺代谢。此外，我们表明抑制谷氨酰胺，无论是通过谷氨酰胺酶（Gls1）的基因缺失还是通过谷氨酰胺酶的药理学抑制，均可在体内导致显著的放射增敏。这导致 Gls1 缺陷型肉瘤小鼠相比 Gls1 正常型肉瘤小鼠的总生存期显著增加。
最后，RT 后 Gls1 缺陷型肉瘤中参与NK 细胞和干扰素 α/γ 反应的蛋白水平升高，提示先天免疫可能在 Gls1 缺陷型肉瘤的放射增敏中发挥作用。
因此，我们的结果表明谷氨酰胺在 RMS 小鼠模型中有助于放射反应。
展开英文摘要原文
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/+ ; Nras LSL-G12D/+ ; p53 fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13 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.
论文信息
- 作者
- Patel R、Cooper DE、Kadakia KT、Allen A、Duan L、Luo L、Williams NT、Liu X
- 第一作者单位
- Department of Radiation Oncology, Baylor College of Medicine, 7200 Cambridge St, Houston, TX, 77030, USA.United States
- 通讯作者单位
- Department of Radiation Oncology, Duke University, Box 3085, Duke Cancer Center, Medicine Circle, Durham, NC, 27710, USA. David.Kirsch@uhn.ca.United States
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究
- 期刊
- Communications biology2024 May 20
- 原文标识
- PubMed 38769385 · DOI 10.1038/s42003-024-06262-x
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