Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells.
Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells.
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DOI：
10.18632/oncotarget.1958
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发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Pastorelli R
中科院分区：
文献类型：
--
作者：
Brunelli L;Caiola E;Marabese M;Broggini M;Pastorelli R
在非小细胞肺癌（NSCLC）中，五分之一的患者有KRAS突变，这被认为是一线治疗的阴性预测因素。有证据表明，并非所有KRAS突变都具有相同的生物学活性，KRAS激活可能导致细胞代谢重塑，这可能使情况复杂化。一个悬而未决的问题是，密码子12处的不同KRAS突变是否会不同地影响细胞代谢，从而可能影响对癌症治疗的不同反应。我们应用了一种探索性的基于质谱的非靶向代谢组学策略，以表征可能区分在密码子12（G12 C，G12 D，G12 V）和野生型过度表达突变形式KRAS的同基因NSCLC细胞的最大可能数量的代谢物。谷氨酰胺剥夺试验和实时PCR用于确认所强调的一些代谢途径的参与。细胞克隆在KRAS野生型和突变体中显示出不同的代谢组学特征。在密码子-12处具有不同KRAS突变的克隆也具有不同的代谢重塑，例如不同的氧化还原缓冲系统和不同的谷氨酰胺依赖性，而不是由参与精氨酸分解的酶的转录状态驱动。这些研究结果表明，KRAS突变在密码子-12与不同的代谢组学特征，可能会影响对癌症治疗的反应。
In non-small-cell lung cancer (NSCLC), one-fifth of patients have KRAS mutations, which are considered a negative predictive factor to first-line therapy. Evidence is emerging that not all KRAS mutations have the same biological activities and possible remodeling of cell metabolism by KRAS activation might complicate the scenario. An open question is whether different KRAS mutations at codon-12 affect cellular metabolism differently with possible implications for different responses to cancer treatments. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish isogenic NSCLC cells overexpressing mutated forms of KRAS at codon-12 (G12C, G12D, G12V) and the wild-type. The glutamine deprivation assay and real-time PCR were used to confirm the involvement of some of the metabolic pathways highlighted. Cell clones indicated distinct metabolomic profiles in KRAS wild-type and mutants. Clones harboring different KRAS mutations at codon-12 also had different metabolic remodeling, such as a different redox buffering system and different glutamine-dependency not driven by the transcriptional state of enzymes involved in glutaminolysis. These findings indicate that KRAS mutations at codon-12 are associated with different metabolomic profiles that might affect the responses to cancer treatments.
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影响因子：
64.5
作者：
Nomura DK;Long JZ;Niessen S;Hoover HS;Ng SW;Cravatt BF
通讯作者：
Cravatt BF
影响因子：
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作者：
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DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
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作者：
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通讯作者：
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DOI：
10.1016/j.jpba.2010.11.038
发表时间：
2011-04-05
影响因子：
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作者：
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通讯作者：
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影响因子：
7.4
作者：
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