Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming.
Acute myeloid leukemia cells require 6-phosphogluconate dehydrogenase for cell growth and NADPH-dependent metabolic reprogramming.
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DOI：
10.18632/oncotarget.18797
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Sattler M
中科院分区：
文献类型：
--
作者：
Bhanot H;Weisberg EL;Reddy MM;Nonami A;Neuberg D;Stone RM;Podar K;Salgia R;Griffin JD;Sattler M
急性髓系白血病(AML)细胞高度依赖糖酵解途径来产生代谢能量和支持细胞生长，这暗示了特定的、可靶向的脆弱性是潜在的药物开发的新靶点。NADPH是一种参与氧化还原反应的中央代谢因子，其水平升高在髓系白血病细胞中很常见，但其背后的意义或生化基础尚不清楚。使用一种有效抑制NADPH产生酶的小分子类似物，我们发现AML细胞需要NADPH动态平衡来实现细胞生长。我们还发现，通过敲除戊糖磷酸途径中的6-磷酸葡萄糖酸脱氢酶(6PGD)来抑制NADPH的产生足以减少细胞生长和乳酸的产生，这是代谢重新编程的一种措施。此外，抑制6PGD活性降低了氧化的NADH依赖的sirtuin-1的NADH水平和酶活性。靶向6PGD和NADPH的产生足以阻止对化疗药物柔红霉素和阿糖胞苷耐药的AML细胞株的生长。重要的是，基质细胞介导的对奎扎替尼靶向抑制致癌Flt3激酶活性的抵抗被6PGD基因敲除所绕过。总体而言，这些数据表明，急性髓细胞白血病细胞对NADPH的依赖导致糖酵解通量增加，这可能产生潜在的治疗益处，因为NADPH的增加很大程度上依赖于单一酶6PGD的活性。
Acute myeloid leukemia (AML) cells are highly dependent on glycolytic pathways to generate metabolic energy and support cell growth, hinting at specific, targetable vulnerabilities as potential novel targets for drug development. Elevated levels of NADPH, a central metabolic factor involved in redox reactions, are common in myeloid leukemia cells, but the significance or biochemical basis underlying this increase is unknown. Using a small molecule analog that efficiently inhibits NADPH-producing enzymes, we found that AML cells require NADPH homeostasis for cell growth. We also found that inhibiting NADPH production through knockdown of 6-phosphogluconate dehydrogenase (6PGD) within the pentose phosphate pathway was sufficient to reduce cell growth and lactate production, a measure of metabolic reprogramming. Further, inhibition of 6PGD activity reduced NADH levels and enzymatic activity of the oxidized NADH-dependent sirtuin-1. Targeting 6PGD and NADPH production was sufficient to block growth of AML cell lines resistant to the chemotherapeutics daunorubicin and cytarabine. Importantly, stromal cell-mediated resistance to targeted inhibition of oncogenic FLT3 kinase activity by quizartinib was circumvented by 6PGD knockdown. Overall, these data suggest that the dependency of AML cells on NADPH to permit increased glycolytic flux creates a potential vulnerability of possible therapeutic benefit, since much of the enhanced production of NADPH is dependent on the activity of a single enzyme, 6PGD.
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DOI：
10.1158/1078-0432.ccr-14-2146
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Alvarez-Calderon F;Gregory MA;Pham-Danis C;DeRyckere D;Stevens BM;Zaberezhnyy V;Hill AA;Gemta L;Kumar A;Kumar V;Wempe MF;Pollyea DA;Jordan CT;Serkova NJ;Graham DK;DeGregori J
通讯作者：
DeGregori J
影响因子：
13.8
作者：
Patra, Krushna C.;Hay, Nissim
通讯作者：
Hay, Nissim
影响因子：
20.3
作者：
Guzman, ML;Rossi, RM;Jordan, CT
通讯作者：
Jordan, CT
影响因子：
3.5
作者：
Caprari, P;Caforio, MP;Salvati, AM
通讯作者：
Salvati, AM
影响因子：
45.3
作者：
Buechner, Thomas;Schlenk, Richard F.;Pfirrmann, Markus
通讯作者：
Pfirrmann, Markus