Increased Glutamine Consumption in Cisplatin-Resistant Cells Has a Negative Impact on Cell Growth.
Increased Glutamine Consumption in Cisplatin-Resistant Cells Has a Negative Impact on Cell Growth.
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顺铂耐药细胞中谷氨酰胺消耗增加对细胞生长产生负面影响
DOI：
10.1038/s41598-018-21831-x
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发表时间：
2018-03-06
影响因子：
4.6
通讯作者：
Zou X
中科院分区：
文献类型：
--
作者：
Duan G;Shi M;Xie L;Xu M;Wang Y;Yan H;Zhuge Y;Zou X
耐药亚克隆的出现仍然是肿瘤治疗失败的主要原因。一些理论认为，耐药细胞的生长可以被药物敏感细胞抑制，因为在没有药物的情况下，耐药细胞比敏感细胞更不适合。我们研究了顺铂(Ddp)耐药细胞和亲本细胞的适合度差异及其潜在机制。我们发现，在DDP抗性细胞中，谷氨酰胺(Gln)的消耗显著高于敏感细胞，这表明在相同的Gln条件下，产生的DDP抗性细胞比敏感细胞要少得多。有趣的是，DDP抗性细胞的抗氧化能力也显著增强，这与Gln的存在有直接关系。然后，我们发现，通过致癌KRAS加速耐药细胞中谷氨酰胺的分解代谢，增强了抗氧化能力。进一步的分析表明，快速的谷氨酰胺分解代谢通过增强抗氧化能力直接介导了对DDP的抗性，但由于增加了谷氨酰胺的分解代谢，相同数量的谷氨酰胺可以产生的最大抗性细胞数量显著减少。总而言之，我们的研究表明，快速的Gln分解代谢为ddp耐药细胞提供了耐受细胞毒治疗的能力，但也由于过量的Gln消耗而阻碍了ddp耐药细胞的生长。
The emergence of drug-resistant subclones remains the primary reason for tumor treatment failure. Some theories suggest that drug-resistant cell growth can be suppressed by drug-sensitive cells because resistant cells are less fit than sensitive cells in the absence of drug. We investigated fitness differences and their underlying mechanisms in cisplatin (ddp)-resistant cells and parental cells. We found that glutamine (Gln) consumption was substantially higher in ddp-resistant cells than that in sensitive cells, indicating that significantly fewer ddp-resistant cells than sensitive cells could be generated under the same Gln conditions. Interestingly, the antioxidant capacity of ddp-resistant cells was also significantly enhanced and was directly related to the presence of Gln. Then, we found that enhanced antioxidant capacity was sustained by accelerated Gln catabolism in resistant cells through oncogenic KRAS. Further analysis indicated that rapid Gln catabolism directly mediated ddp resistance through enhanced antioxidant capacity, but the maximum number of resistant cells that could be produced with the same amount of Gln was significantly reduced due to increased Gln catabolism. Collectively, our study revealed that rapid Gln catabolism provided ddp-resistant cells with the ability to tolerate cytotoxic treatment but also hindered the growth of ddp-resistant cells due to excessive Gln consumption.
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影响因子：
17.1
作者：
Enriquez-Navas PM;Kam Y;Das T;Hassan S;Silva A;Foroutan P;Ruiz E;Martinez G;Minton S;Gillies RJ;Gatenby RA
通讯作者：
Gatenby RA
通过维持一定数量的顺铂敏感细胞来延缓顺铂耐药性发展的策略
影响因子：
4.6
作者：
Duan G;Tang Q;Yan H;Xie L;Wang Y;Zheng XE;Zhuge Y;Shen S;Zhang B;Zhang X;Wang J;Wang W;Zou X
通讯作者：
Zou X
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
64.8
作者：
Waclaw B;Bozic I;Pittman ME;Hruban RH;Vogelstein B;Nowak MA
通讯作者：
Nowak MA
DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME