Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.
Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.
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DOI：
10.1186/s40170-021-00270-9
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发表时间：
2021-09-23
影响因子：
5.9
通讯作者：
Byers LA
中科院分区：
文献类型：
--
作者：
Cargill KR;Stewart CA;Park EM;Ramkumar K;Gay CM;Cardnell RJ;Wang Q;Diao L;Shen L;Fan YH;Chan WK;Lorenzi PL;Oliver TG;Wang J;Byers LA
转录因子 MYC 在 30% 的小细胞肺癌 (SCLC) 肿瘤中过度表达，已知可调节两种主要代谢途径之间的平衡：糖酵解和线粒体呼吸。 MYC 的这种二元性强调了进一步研究其在 SCLC 代谢中的作用的重要性，并可能导致对代谢靶向方法的深入了解。我们根据患者和细胞系样本中的 cMYC 表达，研究了转录和代谢组学数据集中代谢途径的差异。通过流式细胞术和 Seahorse 细胞外通量方法评估代谢途径的利用。使用 PFK158（PFKFB3 的小分子抑制剂）在体外和体内评估糖酵解抑制作用。 MYC 过表达的 SCLC 患者样本和细胞系表现出 MYC 直接介导的糖酵解基因表达增加。此外，MYC 过表达的细胞系表现出与 Warburg 效应一致的糖酵解增强，而 MYC 表达低的细胞系似乎更依赖于氧化代谢。 PFK158 抑制糖酵解优先减弱 MYC 过表达细胞系中的葡萄糖摄取、ATP 产生和乳酸。在异种移植物中使用 PFK158 治疗可延缓肿瘤生长并降低糖酵解基因表达。我们的研究强调了 SCLC 代谢程序的深入表征，并将糖酵解作为 MYC 下游的一种可靶向机制，可以为一小部分 SCLC 患者提供治疗益处。在线版本包含可在 10.1186/s40170-021-00270-9 获取的补充材料。
The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients. The online version contains supplementary material available at 10.1186/s40170-021-00270-9.
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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：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
50.3
作者：
Gay CM;Stewart CA;Park EM;Diao L;Groves SM;Heeke S;Nabet BY;Fujimoto J;Solis LM;Lu W;Xi Y;Cardnell RJ;Wang Q;Fabbri G;Cargill KR;Vokes NI;Ramkumar K;Zhang B;Della Corte CM;Robson P;Swisher SG;Roth JA;Glisson BS;Shames DS;Wistuba II;Wang J;Quaranta V;Minna J;Heymach JV;Byers LA
通讯作者：
Byers LA
影响因子：
158.5
作者：
Horn, L.;Mansfield, A. S.;Liu, S. V.
通讯作者：
Liu, S. V.
影响因子：
16
作者：
Chen, Pei-Hsuan;Cai, Ling;DeBerardinis, Ralph J.
通讯作者：
DeBerardinis, Ralph J.