Acid ceramidase is upregulated in AML and represents a novel therapeutic target.
Acid ceramidase is upregulated in AML and represents a novel therapeutic target.
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DOI：
10.18632/oncotarget.13079
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发表时间：
2016-12-13
期刊：
影响因子：
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通讯作者：
Loughran TP Jr
中科院分区：
文献类型：
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作者：
Tan SF;Liu X;Fox TE;Barth BM;Sharma A;Turner SD;Awwad A;Dewey A;Doi K;Spitzer B;Shah MV;Morad SA;Desai D;Amin S;Zhu J;Liao J;Yun J;Kester M;Claxton DF;Wang HG;Cabot MC;Schuchman EH;Levine RL;Feith DJ;Loughran TP Jr
急性髓性白血病（AML）的新疗法迫切需要得到满足，因为标准疗法在过去三十年中没有改变，大多数患者的结局仍然很差。通过降低神经酰胺水平和升高1-磷酸鞘氨醇（S1 P）的鞘脂失调促进癌细胞生长和存活。酸性神经酰胺酶（AC）催化神经酰胺分解为鞘氨醇（S1 P的前体）。我们首次报告AC是AML原始细胞存活所必需的。转录组分析和酶分析显示原代AML细胞具有高水平的AC表达和活性。用AC抑制剂LCL 204处理患者样品和细胞系降低了活力并诱导了细胞凋亡。AC过表达增加抗凋亡Mcl-1的表达，显著增加S1 P和降低神经酰胺。相反，LCL 204通过翻译后机制诱导神经酰胺积累并降低Mcl-1。LCL 204治疗显著增加了移植有白血病C1498细胞的C57 BL/6小鼠的总体存活率，并显著降低了移植有原代人AML细胞的NSG小鼠的白血病负荷。总的来说，这些研究表明AC通过调节鞘脂水平和Mcl-1在AML生存中起关键作用。我们建议AC作为AML的新治疗靶点值得进一步探索。
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.