High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
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DOI：
10.1016/j.cmet.2020.12.005
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发表时间：
2021-01-05
期刊：
影响因子：
29
通讯作者：
Keshari KR
中科院分区：
文献类型：
--
作者：
Jeong S;Savino AM;Chirayil R;Barin E;Cheng Y;Park SM;Schurer A;Mullarky E;Cantley LC;Kharas MG;Keshari KR
饮食中果糖消耗量的显着增加被认为是癌症的潜在驱动因素。癌细胞利用果糖的代谢适应为其恶性生长提供了优势，但尚未确定令人信服的治疗靶点。在这里，我们表明，白血病细胞的果糖代谢可以通过靶向从头丝氨酸合成途径（SSP）抑制。白血病细胞，不像他们的正常同行，变得显着依赖于SSP在果糖丰富的条件相比，葡萄糖丰富的条件。该代谢程序由氧化还原辅因子NAD+/NADH的比率介导，并且增加的SSP通量有利于从谷氨酰胺产生α-酮戊二酸，这使得白血病细胞即使在没有葡萄糖的情况下也能增殖。在高果糖存在下，抑制SSP中的限速酶PHGDH显著降低小鼠中的白血病植入，证实了SSP在白血病细胞的代谢可塑性中的重要作用。过量的果糖摄入与癌症进展有关，Jeong等人展示了果糖在癌细胞中的意外代谢。急性髓性白血病细胞上调丝氨酸合成途径以代谢果糖衍生的碳，并且靶向PHGDH（丝氨酸合成途径中的限速酶）在高果糖存在下显著降低肿瘤负荷。
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells. Excessive fructose intake has been implicated in cancer progression, and Jeong et al. show an unexpected metabolism of fructose in cancer cells. Acute myeloid leukemic cells upregulate the serine synthesis pathway to metabolize fructose-derived carbons, and targeting PHGDH, a rate limiting enzyme in the serine synthesis pathway, significantly reduces the tumor burden in the presence of high fructose.
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癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
11.4
作者：
Ju HQ;Zhan G;Huang A;Sun Y;Wen S;Yang J;Lu WH;Xu RH;Li J;Li Y;Garcia-Manero G;Huang P;Hu Y
通讯作者：
Hu Y
影响因子：
29
作者：
Jang C;Hui S;Lu W;Cowan AJ;Morscher RJ;Lee G;Liu W;Tesz GJ;Birnbaum MJ;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
56.9
作者：
MAENPAA, PH;RAIVIO, KO;KEKOMAKI, MP
通讯作者：
KEKOMAKI, MP