在KRAS/LKB1突变肺癌细胞中维持胺池和DNA合成
Jiyeon Kim1, Zeping Hu1, Ling Cai1
1Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature
|May 25, 2017
概括
具有KRAS和LKB1突变的侵袭性非小细胞肺癌依赖于碳酸盐合成酶-1 (CPS1) 来合成胺. 通过消耗pyrimidines,抑制CPS1会导致细胞死亡,从而成为潜在的治疗点.
科学领域:
- 癌症学
- 癌症新陈代谢
- 分子生物学
背景情况:
- 包括KRAS突变在内的瘤信号驱动了对癌症发病和进展至关重要的代谢重编程.
- 非小细胞肺癌 (NSCLC) 经常含有KRAS和瘤抑制剂STK11 (编码LKB1) 的突变,同时存在与侵袭性疾病相关的突变 (KL).
- 代谢失调,特别是在处理方面,是KL NSCLC的标志.
研究的目的:
- 研究具有KRAS和LKB1突变的侵袭性非小细胞肺癌 (NSCLC) 的代谢变化.
- 阐明碳酸盐合成酶-1 (CPS1) 在KL NSCLC细胞的代谢中的作用及其对瘤生长的影响.
- 确定与KL NSCLC中观察到的代谢重编程相关的潜在治疗漏洞.
主要方法:
- 对人类KL细胞和瘤进行比较的代谢分析,以确定乱的代谢途径.
- 研究碳酸盐合成酶-1 (CPS1) 表达及其通过LKB1/AMPK信号的调节.
- 功能性研究涉及KL细胞中CPS1沉默和外源性胺补充剂,以评估细胞死亡,瘤生长和DNA损伤.
主要成果:
- KL细胞和瘤表现出独特的代谢特征,其特征是改变处理,包括carbamoyl phosphate synthetase-1 (CPS1) 的表达.
- LKB1通过AMPK抑制CPS1转录;CPS1表达与人类NSCLC中的LKB1水平相反相关.
- 在KL细胞中抑制CPS1导致细胞死亡,而不是氨毒性,并通过破坏DNA合成和导致DNA损伤来减少瘤生长.
结论:
- 这种KL瘤基因型在侵袭性NSCLC中产生了代谢脆弱性,依赖于非传统的-胺代谢途径.
- 在KL NSCLC中,CPS1在快速细胞增殖中发挥着关键作用.
- 针对CPS1或胺合成途径代表了对这种侵袭性NSCLC的有希望的治疗策略.
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