Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.
Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells.
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DOI：
10.1158/0008-5472.can-16-1645
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发表时间：
2017-03-15
期刊：
影响因子：
11.2
通讯作者：
Andreeff M
中科院分区：
文献类型：
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作者：
Tabe Y;Yamamoto S;Saitoh K;Sekihara K;Monma N;Ikeo K;Mogushi K;Shikami M;Ruvolo V;Ishizawa J;Hail N Jr;Kazuno S;Igarashi M;Matsushita H;Yamanaka Y;Arai H;Nagaoka I;Miida T;Hayashizaki Y;Konopleva M;Andreeff M
骨髓（BM）中的白血病细胞必须满足细胞增殖增加的生化要求，并通过不断适应营养和氧气可用性的波动而存活。因此，靶向位于BM中的白血病细胞中的代谢异常是一种新的治疗方法。在本研究中，我们研究了BM脂肪细胞在支持白血病母细胞生长中的代谢作用。使用各种分析技术研究了BM脂肪细胞对营养饥饿诱导的白血病细胞凋亡的预防，以及参与这一过程的代谢和分子机制。在急性单核细胞白血病（阿莫尔）细胞中，BM脂肪细胞对自发性凋亡的预防与脂肪酸β-氧化（FAO）增加以及PPARγ、FABP 4、CD 36和BCL 2基因上调沿着相关。在阿莫尔细胞中，BM脂肪细胞共培养增加脂联素受体基因表达及其下游靶向应激反应激酶AMPK、p38 MAPK与自噬激活，并上调抗凋亡分子伴侣热休克蛋白。FAO的抑制破坏了代谢稳态，增加了活性氧的产生，诱导了整合的应激反应介质ATF 4，以及与BM脂肪细胞共培养的阿莫尔细胞的凋亡。我们的研究结果表明，BM脂肪细胞通过调节其代谢能量平衡来支持阿莫尔细胞的存活，并且破坏BM脂肪细胞中的FAO可能是阿莫尔治疗的一种替代的新型治疗策略。
Leukemia cells in the bone marrow (BM) must meet the biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the BM is a novel therapeutic approach. In the present study, we investigated the metabolic role of BM adipocytes in supporting the growth of leukemic blasts. Prevention of nutrient starvation-induced apoptosis of leukemic cells by BM adipocytes, as well as the metabolic and molecular mechanisms involved in this process, were investigated using various analytical techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by BM adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with the upregulation of PPARγ, FABP4, CD36, and BCL2 genes. In AMoL cells, BM adipocyte co-culture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone heat shock proteins. Inhibition of FAO disrupted metabolic homeostasis, increased reactive oxygen species production, induced the integrated stress response mediator ATF4, and apoptosis in AMoL cells co-cultured with BM adipocytes. Our results suggest that BM adipocytes support AMoL cell survival by regulating their metabolic energy balance, and that the disruption of FAO in BM adipocytes may be an alternative, novel therapeutic strategy for AMoL therapy.