Hexosamine Biosynthetic Pathway Inhibition Leads to AML Cell Differentiation and Cell Death.
Hexosamine Biosynthetic Pathway Inhibition Leads to AML Cell Differentiation and Cell Death.
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DOI：
10.1158/1535-7163.mct-18-0426
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发表时间：
2018-10
影响因子：
5.7
通讯作者：
Parameswaran R
中科院分区：
文献类型：
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作者：
Asthana A;Ramakrishnan P;Vicioso Y;Zhang K;Parameswaran R
急性髓性白血病（AML）的治疗在过去40年中保持不变。靶向细胞代谢是未来癌症治疗的一个有前途的途径。我们发现，参与代谢氨基己糖生物合成途径（HBP）的酶在AML患者中增加。抑制GFAT（HBP的限速酶）诱导AML细胞分化和凋亡，而不影响正常细胞。UDP-GlcNAc是HBP的终产物，是O-GlcNAc酰化（一种翻译后修饰）的底物。O-GlcNAc转移酶（OGT）是将GlcNAc从UDP-GlcNAc转移到靶蛋白的酶。使用OGT抑制剂抑制O-GlcNAc化以及基因敲低OGT也导致AML细胞的细胞分化和凋亡。最后，体内HBP抑制减少了皮下AML异种移植模型中的肿瘤生长，并且肿瘤细胞显示出体内分化的迹象。循环AML异种移植模型也显示在HBP抑制后骨髓、脾和血液中的肿瘤负荷的清除，没有全身毒性的迹象。这项研究揭示了HBP/O-GlcNAc化在保持AML细胞处于未分化状态中的重要作用，并揭示了通过HBP/O-GlcNAc抑制潜在AML治疗的新领域。
Treatment for Acute myeloid leukemia (AML) has remained unchanged for past 40 years. Targeting cell metabolism is a promising avenue for future cancer therapy. We found that enzymes involved in metabolic hexosamine biosynthetic pathway (HBP) are increased in AML patients. Inhibiting GFAT (the rate limiting enzyme of HBP) induced differentiation and apoptosis in AML cells, sparing normal cells. UDP-GlcNAc, the end product of HBP, is the substrate for O-GlcNAcylation, a post-translational modification. O-GlcNAc transferase (OGT) is the enzyme which transfers GlcNAc from UDP-GlcNAc to target proteins. Inhibition of O-GlcNAcylation, using OGT inhibitors as well as genetic knockdown of OGT, also led to cell differentiation and apoptosis of AML cells. Finally, HBP inhibition in vivo, reduced the tumor growth in a sub-cutaneous AML xenograft model and tumor cells showed signs of differentiation in vivo. A circulating AML xenograft model also showed clearance of tumor load in bone marrow, spleen and blood, after HBP inhibition, with no signs of general toxicity. This study reveals an important role of HBP/O-GlcNAcylation in keeping AML cells in an undifferentiated state and sheds light into a new area of potential AML therapy by HBP/O-GlcNAc inhibition.