AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.
AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.
复制标题
DOI：
10.1182/bloodadvances.2022007383
复制
发表时间：
2023-05-09
期刊：
影响因子：
7.5
通讯作者：
Guikema, Jeroen E. J.
中科院分区：
文献类型：
--
作者：
Bloedjes, Timon A.;de Wilde, Guus;Khan, Gerarda H.;Ashby, Timothy C.;Shaughnessy Jr, John D.;Zhan, Fenghuang;Houtkooper, Riekelt H.;Bende, Richard J.;van Noesel, Carel J. M.;Spaargaren, Marcel;Guikema, Jeroen E. J.
AKT通过限制FOXO来防止多发性骨髓瘤细胞的代谢关闭。代谢基因的FOXO依赖性抑制与MM的良好预后相关。代谢改变是重要的癌症相关特征，允许癌细胞在应激条件下转化和存活。多发性骨髓瘤（MM）浆细胞显示糖酵解和氧化磷酸化（OXPHOS）增加，这是与驱动MM细胞增殖和存活的复发性遗传畸变相关的特征。蛋白激酶B/AKT在细胞代谢中起中心节点的作用，并且在MM细胞中具有组成性活性。尽管已知AKT在调节细胞代谢中的作用，但对控制MM细胞代谢适应性的AKT下游因子知之甚少。在这里，我们证明了AKT对叉头框O（FOXO）转录因子（TF）的负调控对于防止MM细胞的代谢关闭至关重要，从而有助于其代谢适应性。我们的研究结果表明，参与糖酵解，三羧酸（TCA）循环和OXPHOS的几个关键代谢基因的表达被FOXO TF抑制。此外，FOXO依赖性抑制糖酵解和TCA相关基因与一个良好的预后在一个大型队列的MM患者。我们的数据表明，抑制FOXO的AKT是必不可少的维持糖酵解和TCA循环活动在MM细胞，因此，预测患者的生存。
AKT prevents the metabolic shutdown of multiple myeloma cells by restricting FOXO. FOXO-dependent repression of metabolic genes is associated with favorable prognosis in MM. Metabolic alterations are important cancer-associated features that allow cancer cell transformation and survival under stress conditions. Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), which are characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. Despite the known role of AKT in modulating cellular metabolism, little is known about the downstream factors of AKT that control the metabolic adaptability of MM cells. Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TFs) by AKT is crucial to prevent the metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and OXPHOS are repressed by FOXO TFs. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large cohort of patients with MM. Our data suggest that repression of FOXO by AKT is essential to sustain glycolysis and the TCA cycle activity in MM cells and, as such, predicts patient survival.
登录
查看更多内容
用FDA批准的利托那韦和二甲双胍靶向多发性骨髓瘤的代谢可塑性。
DOI：
10.1158/1078-0432.ccr-14-1088
发表时间：
2015-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dalva-Aydemir S;Bajpai R;Martinez M;Adekola KU;Kandela I;Wei C;Singhal S;Koblinski JE;Raje NS;Rosen ST;Shanmugam M
通讯作者：
Shanmugam M
影响因子：
20.3
作者：
Hsu, JH;Shi, YJ;Lichtenstein, A
通讯作者：
Lichtenstein, A
影响因子：
6.5
作者：
Shaughnessy JD;Zhou Y;Haessler J;van Rhee F;Anaissie E;Nair B;Waheed S;Alsayed Y;Epstein J;Crowley J;Barlogie B
通讯作者：
Barlogie B
影响因子：
11.4
作者：
Bouchard, C;Marquardt, J;Eilers, M
通讯作者：
Eilers, M
影响因子：
3.7
作者：
Aguer C;Gambarotta D;Mailloux RJ;Moffat C;Dent R;McPherson R;Harper ME
通讯作者：
Harper ME