Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
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DOI：
10.1186/s40364-022-00367-3
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发表时间：
2022-04-02
影响因子：
11.1
通讯作者：
Cao H
中科院分区：
文献类型：
--
作者：
Xu Y;Hino C;Baylink DJ;Xiao J;Reeves ME;Zhong JF;Mirshahidi S;Cao H
急性髓细胞白血病（AML）是白血病中生存率最低的一种。靶向白血病细胞中的细胞内代谢和能量产生可以是AML的有希望的治疗策略。最近，我们提出了成功地使用维生素D（1，25 VD 3）基因疗法治疗AML小鼠模型在体内。在这项研究中，认识到1，25 VD 3作为在这个星球上生命的开始阶段期间光合作用获得能量的仅有的2种分子（沿着葡萄糖）之一的重要性，我们探索了1，25 VD 3在AML代谢中的功能作用。四种不同AML细胞系的转录组数据库（RNA-seq）揭示了17，757个响应于1，25 VD 3处理的基因。此外，我们发现果糖二磷酸酶1（FBP 1）是唯一一个基因（在17，757个基因中），基因表达增加了250倍，已知编码关键限速酶果糖-1，6-二磷酸酶。通过qPCR、western blot、流式细胞术、免疫细胞化学和功能性乳酸测定证实了1，25 VD 3诱导的FBP 1基因和蛋白的表达显著增加。此外，发现1，25 VD 3调节不同的AML代谢过程，包括造血、糖酵解、TCA、从头核苷酸合成等。总之，我们提供了第一个证据，表明1，25 VD 3诱导的FBP 1过表达可能是阻断“瓦尔堡效应”以减少AML原始细胞能量产生的新治疗靶点。在线版本包含补充材料，可通过10.1186/s40364-022-00367-3获得。
Acute myeloid leukemia (AML) has the lowest survival rate among the leukemias. Targeting intracellular metabolism and energy production in leukemic cells can be a promising therapeutic strategy for AML. Recently, we presented the successful use of vitamin D (1,25VD3) gene therapy to treat AML mouse models in vivo. In this study, recognizing the importance of 1,25VD3 as one of only 2 molecules (along with glucose) photosynthesized for energy during the beginning stage of life on this planet, we explored the functional role of 1,25VD3 in AML metabolism. Transcriptome database (RNA-seq) of four different AML cell lines revealed 17,757 genes responding to 1,25VD3-treatment. Moreover, we discovered that fructose-bisphosphatase 1 (FBP1) noticeably stands out as the only gene (out of 17,757 genes) with a 250-fold increase in gene expression, which is known to encode the key rate-limiting gluconeogenic enzyme fructose-1,6-bisphosphatase. The significant increased expression of FBP1 gene and proteins induced by 1,25VD3 was confirmed by qPCR, western blot, flow cytometry, immunocytochemistry and functional lactate assay. Additionally, 1,25VD3 was found to regulate different AML metabolic processes including gluconeogenesis, glycolysis, TCA, de novo nucleotide synthesis, etc. In summary, we provided the first evidence that 1,25 VD3-induced FBP1 overexpression might be a novel therapeutic target to block the “Warburg Effect” to reduce energy production in AML blasts. The online version contains supplementary material available at 10.1186/s40364-022-00367-3.
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影响因子：
11.4
作者：
Simonetti G;Mengucci C;Padella A;Fonzi E;Picone G;Delpino C;Nanni J;De Tommaso R;Franchini E;Papayannidis C;Marconi G;Pazzaglia M;Perricone M;Scarpi E;Fontana MC;Bruno S;Tebaldi M;Ferrari A;Bochicchio MT;Ghelli Luserna Di Rorà A;Ghetti M;Napolitano R;Astolfi A;Baldazzi C;Guadagnuolo V;Ottaviani E;Iacobucci I;Cavo M;Castellani G;Haferlach T;Remondini D;Capozzi F;Martinelli G
通讯作者：
Martinelli G
DOI：
10.1016/j.jsbmb.2019.105399
发表时间：
2019-09-01
影响因子：
4.1
作者：
Maia-Ceciliano, Thais C.;Dutra, Rafaela R.;Mandarim-De-Lacerda, Carlos A.
通讯作者：
Mandarim-De-Lacerda, Carlos A.
影响因子：
4.7
作者：
Marchwicka A;Cebrat M;Sampath P;Snieżewski L;Marcinkowska E
通讯作者：
Marcinkowska E
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
23.9
作者：
Jones CL;Inguva A;Jordan CT
通讯作者：
Jordan CT