Reactive Oxygen Species Drive Proliferation in Acute Myeloid Leukemia via the Glycolytic Regulator PFKFB3.
Reactive Oxygen Species Drive Proliferation in Acute Myeloid Leukemia via the Glycolytic Regulator PFKFB3.
复制标题
DOI：
10.1158/0008-5472.can-19-1920
复制
发表时间：
2020-03-01
期刊：
影响因子：
11.2
通讯作者：
Tonks A
中科院分区：
文献类型：
--
作者：
Robinson AJ;Hopkins GL;Rastogi N;Hodges M;Doyle M;Davies S;Hole PS;Omidvar N;Darley RL;Tonks A
急性髓系白血病(AML)是一种临床预后较差的异质性克隆性疾病。在此之前，我们发现60%的AML患者体内存在由NOX2氧化酶结构性激活引起的ROS的过度产生，ROS的产生促进了AML细胞的增殖。我们在这里表明，受ROS过量生产影响最大的过程是糖酵解。对20例人类原发AML的全代谢组分析表明，产生高水平ROS的原始细胞增加了葡萄糖摄取，相应地增加了葡萄糖代谢。为了支持这一点，外源ROS增加了葡萄糖消耗，而抑制NOX2氧化酶则减少了葡萄糖消耗。在机制上，ROS促进解偶联蛋白2(UCP2)的蛋白表达和AMPK的磷酸化，上调关键调节糖酵解酶6-phosphofructo-2-kinase/fructose-2，6-bisphosphatase(PFKFB3)的表达。在NSG模型中，过表达PFKFB3促进葡萄糖摄取和细胞增殖，而下调PFKFB3在体外和体内都强烈抑制白血病的生长。这些实验提供了直接证据，证明氧化物酶衍生的ROS通过糖酵解调节因子PFKFB3促进白血病细胞的生长。因此，靶向PFKFB3可能为这种疾病提供了一种新的治疗模式，但结果不佳。
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder with a poor clinical outcome. Previously we showed that overproduction of reactive oxygen species (ROS), arising from constitutive activation of NOX2 oxidase, occurs in >60% of AML patients and that ROS production promotes proliferation of AML cells. We show here that the process most significantly affected by ROS overproduction is glycolysis. Whole metabolome analysis of 20 human primary AML showed that blasts generating high levels of ROS have increased glucose uptake and correspondingly increased glucose metabolism. In support of this, exogenous ROS increased glucose consumption whilst inhibition of NOX2 oxidase decreased glucose consumption. Mechanistically, ROS promoted uncoupling protein 2 (UCP2) protein expression and phosphorylation of AMPK, upregulating the expression of a key regulatory glycolytic enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Overexpression of PFKFB3 promoted glucose uptake and cell proliferation, whilst downregulation of PFKFB3 strongly suppressed leukemia growth both in vitro and in vivo in the NSG model. These experiments provide direct evidence that oxidase-derived ROS promotes the growth of leukemia cells via the glycolytic regulator PFKFB3. Targeting PFKFB3 may therefore present a new mode of therapy for this disease with a poor outcome.