代谢重编程有助于通过蛋白激酶Cδδ的辐射保护
Angela M Ohm1, Trisiani Affandi1, Julie A Reisz2
1Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
蛋白激酶Cδ (PKCδ) 活性的丧失通过重编程细胞代谢来赋予放射电阻. 枯竭的PKCδ增强了酸通路和谷氨用于核酸合成的利用,有助于细胞抗击DNA损伤的生存.
科学领域:
- 细胞生物学 细胞生物学
- 代谢途径 代谢途径
- 辐射生物学 辐射生物学
背景情况:
- 蛋白质激酶Cδ (PKCδ) 的损失使得DNA对辐射等破坏性物质产生抵抗力.
- 这种放射电阻的潜在机制尚未完全理解.
- 代谢重编程是细胞抵抗的潜在贡献者.
研究的目的:
- 调查PKCδ的代谢重编程是否有助于辐射保护.
- 阐明PKCδ介导的放射电阻所涉及的特定代谢途径.
主要方法:
- 全球代谢学分析,以评估代谢途径的改变.
- 稳定同位素追踪 (使用U-[13C6]葡萄糖和[13C5,15N2]谷氨酸) 来追踪代谢流动.
- 对酸通路 (PPP) 激活,核酸和谷氨生物合成,糖解和氧化酸化的测试.
- 针对PPP和谷氨酸胺酶的抑制研究,以评估它们在辐射保护中的作用.
主要成果:
- PKCδ的枯竭改变了代谢途径,影响了能量生产,抗氧化剂,核酸和氨基酸生物合成.
- 增加PKCδ枯竭细胞中的NADPH和核酸产量与PPP上调相关 (由G6PD激活和增加的5-基-1-酸盐证明).
- 同位素追踪显示,减少了葡萄糖用于糖解的利用,但增加了谷氨酸用于核酸,谷氨和PKCδ贫乏细胞中TCA中间合成的使用.
- 缺乏PKCδ的细胞显示了无氧糖解的增加,氧化酸化的减少,并且在辐射后对PPP和谷氨胺的生存依赖.
结论:
- 当PKCδ被抑制时,代谢重编程,特别是增加谷氨胺利用率和核酸合成,有助于辐射保护.
- 酸通路和谷氨酸代谢对于暴露于辐射的PKCδ贫乏细胞的生存至关重要.
- 准PPP或谷氨酸酶可以逆转PKCδ枯竭细胞中观察到的放射电阻.
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