Small is beautiful-a glycolytic metabolite signals mTORC1 activation in cancer cell metabolism.
Small is beautiful-a glycolytic metabolite signals mTORC1 activation in cancer cell metabolism.
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小是美丽的-A糖酵解代谢物信号MTORC1在癌细胞代谢中的激活。
DOI：
10.1038/s41392-020-00371-9
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发表时间：
2020-11-03
影响因子：
39.3
通讯作者：
Otto AM
中科院分区：
文献类型：
--
作者：
Otto AM
尽管mTOR复合物几十年来一直被认为是一种营养传感器，因此成为代谢疾病和癌症代谢中药物靶向的焦点，但它如何能够获得细胞中葡萄糖可用性的感觉仍然令人困惑。现在，Sabatini和他的同事已经确定了糖酵解途径的一种小代谢产物，二羟丙酮磷酸盐，他们展示了mTORC 1活性如何在葡萄糖饥饿和补充的癌细胞中受到调节。在正常组织和癌症的微环境中，营养波动是不可避免的，细胞必须快速适应其能量代谢，而不需要翻译和转录活动。能量状态的经典传感器是AMP激活的激酶（AMPK），其被高AMP/ATP比率激活并刺激葡萄糖代谢。另一种是mTORC 1，它也被称为氨基酸和脂质代谢的调节剂。2，3尽管它与转录因子相互作用，例如HIF 1和c-myc，其表达可以间接调节癌细胞中的葡萄糖代谢，4葡萄糖代谢的动力学如何调节mTORC 1激活尚未达成共识; AMPK依赖性和独立途径已被假定。2什么是将葡萄糖供应转化为调节代谢信号的代谢成分？为了找到与基于mTORC 1的调节的直接联系，一种不依赖AMPK的调节，Sabatini和同事1开发了一种基因工程肿瘤细胞系统，其中AMPK的表达被敲除，细胞必须依赖于mTORC 1进行葡萄糖感知。当这些细胞缺乏葡萄糖时，mTORC 1的活性（以S6-激酶的磷酸化来测量）几乎检测不到，而加入生理低水平的葡萄糖则会重新激活mTORC 1。使用这种设置的原理，通过逐个条件性敲除或抑制特定酶来剖析连续糖酵解反应的贡献（图1）。在细胞摄取糖后，糖酵解过程由己糖激酶（HK）启动，己糖激酶是一种限速酶，其磷酸化葡萄糖以及果糖，但不磷酸化甘露糖。然而，mTORC 1被激活的所有三种糖时，送达葡萄糖饥饿的细胞;这证实了mTORC 1可以作为一个糖传感器独立的AMPK和刺激不仅由葡萄糖。接下来，敲除葡萄糖-6-磷酸异构酶（GPI），从而中断果糖-6-磷酸的形成，与甘露糖相反，不允许葡萄糖激活mTORC 1-;这表明需要这种磷酸化的中间体。当敲除醛缩酶时，再次没有mTORC 1的激活，代谢物谱显示其下游代谢物磷酸二羟丙酮（DHAP）和磷酸甘油醛（GAP）以及磷酸烯醇丙酮酸（PEP）的水平非常低。值得注意的是，磷酸果糖激酶（PFK），为醛缩酶提供底物，是糖酵解中的关键限速酶;但其底物或其产物果糖-1，6-磷酸的增加都不影响mTORC 1活性。在糖酵解的下部，一个关键酶是甘油醛脱氢酶（GAPDH）（图1），它将GAP氧化为1，3-二磷酸甘油酸，同时将NAD+转化为NADH。当它的活性抑制康宁酸在葡萄糖饥饿的开始，mTORC 1保持激活了一段时间，而上游代谢产物的水平增加，下游代谢产物的水平下降。另一方面，在长时间的葡萄糖饥饿后，在细胞中短暂地用葡萄糖喂养细胞。
Even though the mTOR complex has been known for decades as a nutrient sensor, being thus in focus for drug targeting in metabolic disease and cancer metabolism, it has remained puzzling how it is able to get a sense of glucose availability in cells. Now, a small metabolite of the glycolytic pathway, dihydroxyacetone phosphate, has been identified by Sabatini and his coworkers, who show how mTORC1-activity is regulated in glucose-starved and replenished cancer cells. 1 In a microenvironment of normal tissues and cancers, nutrient fluctuations are inevitable, a condition to which cells must quickly adapt their energy metabolism—without requiring translational and transcriptional activities. A classical sensor of the energy status is AMP-activated kinase (AMPK), which is activated by high AMP/ATP ratios and stimulates glucose metabolism. Another is mTORC1, which is also known as a regulator for amino acid and lipid metabolism. 2, 3 In spite of its interaction with transcription factors, for example, HIF1 and c-myc, whose expression can indirectly regulate glucose metabolism in cancer cells, 4 there has been no consensus on how the dynamics of glucose metabolism regulate mTORC1 activation; both AMPK-dependent and independent pathways have been postulated. 2 What could be a metabolic component for translating glucose supply into signals regulating metabolism? To find a direct link to mTORC1-based regulation, one that is AMPK-independent, Sabatini and coworkers 1 developed a genetically engineered tumor cell system, in which the expression of AMPK was knocked out and the cells had to rely on mTORC1 for glucose sensing. When such cells were starved for glucose, mTORC1 activity, measured as phosphorylation of S6-kinase, was almost undetectable, while the addition of glucose at physiologically low levels reactivated mTORC1. Using the principle of this setup, the contribution of sequential glycolytic reactions was dissected by conditionally knocking out or inhibiting specific enzymes one by one (Fig. 1). Upon cellular uptake of sugars, the glycolytic process is initiated by hexokinase (HK), a rate-limiting enzyme, which phosphorylates glucose as well as fructose, but not mannose. Nevertheless, mTORC1 was activated by all three sugars when served to glucose-starved cells; this confirms that mTORC1 can act as a sugar sensor independently of AMPK and is stimulated not only by glucose. Next, knocking out glucose-6-phosphate isomerase (GPI), thereby interrupting the formation of fructose-6-phosphate, did not allow glucose to activate mTORC1—in contrast to mannose; this indicated that this phosphorylated intermediate is required. When knocking out aldolase, again there was no activation of mTORC1, and metabolite profiling revealed very low levels of its downstream metabolites dihydroxyacetone phosphate (DHAP) and glyceraldehyde phosphate (GAP), but also of phosphoenol pyruvate (PEP). 1 It is noteworthy that phosphofructokinase (PFK), providing the substrate for aldolase, is a key rate-limiting enzyme in glycolysis; but neither its substrate nor an increase in its product fructose-1, 6-phosphate affected mTORC1 activity. In the lower part of glycolysis, a key enzyme is glyceraldehyde dehydrogenase (GAPDH)(Fig. 1), oxidizing GAP to 1, 3-bisphosphate glycerate while converting NAD+ to NADH. When its activity was inhibited by koningic acid at the onset of glucose starvation, mTORC1 remained activated for some time, while the levels of upstream metabolites increased and those of downstream metabolites decreased. On the other hand, after prolonged glucose-starvation, feeding the cells briefly with glucose in the …
影响因子：
20.8
作者：
Orozco JM;Krawczyk PA;Scaria SM;Cangelosi AL;Chan SH;Kunchok T;Lewis CA;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.5
作者：
Saxton RA;Sabatini DM
通讯作者：
Sabatini DM