Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.
Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis.
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DOI：
10.1371/journal.pgen.1002573
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Nilsson JA
中科院分区：
文献类型：
--
作者：
Nilsson LM;Forshell TZ;Rimpi S;Kreutzer C;Pretsch W;Bornkamm GW;Nilsson JA
c-Myc（以下简称Myc）属于调节细胞生长、细胞增殖和分化的转录因子家族。Myc通过刺激代谢和蛋白质合成来启动大量参与细胞生长的基因的转录。其中一些，如涉及糖酵解的那些，可能是Warburg效应的一部分，它被定义为在氧气供应充足的情况下增加葡萄糖摄取和乳酸生成。在这项研究中，我们采用小鼠遗传学方法来挑战myc调节的代谢酶在体内肿瘤发生中的作用。通过将携带乳酸脱氢酶A （Ldha）、3-磷酸甘油酸脱氢酶（Phgdh）和丝氨酸羟甲基转移酶1 （Shmt1）失活等位基因的小鼠模型与λ-Myc转基因小鼠、Apc Min小鼠和p53敲除小鼠进行杂交，获得了监测肿瘤发展的后代。非常令人惊讶的是，我们发现这些基因在这些遗传环境中对于肿瘤的发生是不可或缺的。然而，在表达致癌Ras的成纤维细胞和结肠癌细胞中进行的实验表明，这些细胞对Ldha敲除敏感。我们的遗传模型揭示了细胞环境依赖性和肿瘤细胞适应关键代谢途径变化的显著能力。因此，为了取得临床成功，正确地对患者进行分层并找到针对代谢酶的抑制剂的合成致死组合将是重要的。当细胞改变它们的行为并开始以不受控制的方式分裂时，癌症就发生了。为了实现这种行为的改变，细胞需要改变它们的新陈代谢，以便在营养和氧气供应有限的情况下也能生长。因此，靶向代谢途径可以用于治疗癌症患者。在这里，我们研究了一种叫做MYC的基因，它可以调节许多代谢途径。通过使用转基因小鼠，我们可以证明肿瘤具有改变其代谢的非凡能力，即使关键的酶被移除。综上所述，我们的数据表明，在临床上，药物引起的代谢紊乱可能会带来未来的挑战。
c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply. In this study, we have taken a mouse-genetics approach to challenge the role of select Myc-regulated metabolic enzymes in tumorigenesis in vivo. By breeding λ-Myc transgenic mice, Apc Min mice, and p53 knockout mice with mouse models carrying inactivating alleles of Lactate dehydrogenase A (Ldha), 3-Phosphoglycerate dehydrogenase (Phgdh) and Serine hydroxymethyltransferase 1 (Shmt1), we obtained offspring that were monitored for tumor development. Very surprisingly, we found that these genes are dispensable for tumorigenesis in these genetic settings. However, experiments in fibroblasts and colon carcinoma cells expressing oncogenic Ras show that these cells are sensitive to Ldha knockdown. Our genetic models reveal cell context dependency and a remarkable ability of tumor cells to adapt to alterations in critical metabolic pathways. Thus, to achieve clinical success, it will be of importance to correctly stratify patients and to find synthetic lethal combinations of inhibitors targeting metabolic enzymes. Cancer occurs when cells change their behavior and start to divide in an uncontrolled manner. To achieve this altered behavior, cells need to change their metabolism to be able to grow even when nutrient and oxygen supplies are limiting. Therefore, targeting metabolic pathways could be used to treat patients suffering from cancer. Here we studied a gene called MYC, which can regulate many metabolic pathways. By using genetically modified mice we can show that tumors have a remarkable ability to change their metabolism, even if key enzymes are removed. Taken together, our data suggest that metabolic disturbance by drugs in the clinic may present a future challenge.
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影响因子：
64.5
作者：
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