Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine.
Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine.
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DOI：
10.1038/s41598-018-35198-6
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发表时间：
2018-11-15
影响因子：
4.6
通讯作者：
Konopleva M
中科院分区：
文献类型：
--
作者：
Tabe Y;Saitoh K;Yang H;Sekihara K;Yamatani K;Ruvolo V;Taka H;Kaga N;Kikkawa M;Arai H;Miida T;Andreeff M;Spagnuolo PA;Konopleva M
脂肪细胞是成人骨髓 (BM) 中常见的基质细胞类型，白血病细胞不断适应营养缺乏，在 BM 微环境中获得化学抗性。我们之前已经表明，脂肪酸代谢是急性髓系白血病（AML）细胞在脂肪细胞丰富的骨髓微环境中生存的关键能量途径。新型脂肪酸 β-氧化 (FAO) 抑制剂牛油素 B（一种源自牛油果果实的奇数碳脂）可诱导单一培养的 AML 细胞凋亡和生长抑制。在与 BM 脂肪细胞共培养的 AML 细胞中，用鳄梨素 B 抑制 FAO，通过上调 FABP4 mRNA、增强葡萄糖摄取并转变为糖酵解来适应性刺激游离脂肪酸 (FFA) 摄取。这些变化反映了对线粒体 FFA 供应短缺的代偿反应，并有助于在 BM 脂肪细胞存在的情况下保护 AML 细胞免受鳄梨素 B 诱导的细胞凋亡。然而，在BM脂肪细胞共培养条件下，牛油素B和常规抗AML治疗剂阿糖胞苷（AraC）的联合治疗增加了活性氧，并表现出对AML细胞的高度协同作用。这些发现凸显了 AraC 和 FAO 抑制剂联合治疗方案针对骨髓耐药 AML 细胞的潜力。
Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), and leukemia cells continuously adapt to deficiency of nutrients acquiring chemoresistant profiles in the BM microenvironment. We have previously shown that fatty acid metabolism is a key energy pathway for survival of acute myeloid leukemia (AML) cells in the adipocyte-abundant BM microenvironment. The novel fatty acid β-oxidation (FAO) inhibitor avocatin B, an odd-numbered carbon lipid derived from the avocado fruit, induced apoptosis and growth inhibition in mono-cultured AML cells. In AML cells co-cultured with BM adipocytes, FAO inhibition with avocatin B caused adaptive stimulation of free fatty acid (FFA) uptake through upregulation of FABP4 mRNA, enhanced glucose uptake and switch to glycolysis. These changes reflect the compensatory response to a shortage of FFA supply to the mitochondria, and facilitate the protection of AML cells from avocatin B–induced apoptosis in the presence of BM adipocytes. However, the combination treatment of avocatin B and conventional anti-AML therapeutic agent cytarabine (AraC) increased reactive oxygen species and demonstrated highly synergistic effects on AML cells under BM adipocyte co-culture condition. These findings highlight the potential for combination regimens of AraC and FAO inhibitors that target bone marrow-resident chemoresistant AML cells.
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影响因子：
23.9
作者：
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影响因子：
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影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
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影响因子：
7.3
作者：
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