Targeting N-myristoylation for therapy of B-cell lymphomas.
Targeting N-myristoylation for therapy of B-cell lymphomas.
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DOI：
10.1038/s41467-020-18998-1
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发表时间：
2020-10-22
影响因子：
16.6
通讯作者：
Berthiaume LG
中科院分区：
文献类型：
--
作者：
Beauchamp E;Yap MC;Iyer A;Perinpanayagam MA;Gamma JM;Vincent KM;Lakshmanan M;Raju A;Tergaonkar V;Tan SY;Lim ST;Dong WF;Postovit LM;Read KD;Gray DW;Wyatt PG;Mackey JR;Berthiaume LG
肉豆蔻酰化是蛋白质的N-末端修饰，具有脂肪酸肉豆蔻酸酯，对于膜靶向和细胞信号传导至关重要。由于癌细胞通常具有增加的N-肉豆蔻酰转移酶（NMT）表达，因此提出NMT作为抗癌靶标。为了系统地研究这一点，我们进行了机器人癌细胞系筛选，发现血液癌细胞系（包括B细胞淋巴瘤）对强效泛NMT抑制剂PCLX-001具有显著的敏感性。PCLX-001治疗影响淋巴瘤细胞蛋白的整体豆蔻酰化，并抑制对生存至关重要的早期B细胞受体（BCR）信号传导事件。除了消除Src家族激酶的豆蔻酰化外，PCLX-001还促进其降解，并且出乎意料地促进许多非豆蔻酰化BCR效应物（包括c-Myc、NFκB和P-ERK）的降解，导致体外和异种移植模型中的癌细胞死亡。因为一些治疗的淋巴瘤患者经历复发和死亡，用NMT抑制剂靶向B细胞淋巴瘤可能为淋巴瘤提供额外的急需的治疗选择。N-肉豆蔻酰转移酶（NMT）将许多信号蛋白靶向至膜。在这里，作者展示了一种名为PCLX-001的NMT抑制剂通过关闭淋巴瘤细胞的主要生存信号通路来选择性地杀死淋巴瘤细胞，并为淋巴瘤患者提供了一种额外的治疗策略。
Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma. N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.
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影响因子：
16.6
作者：
Dian, Cyril;Perez-Dorado, Inmaculada;Giglione, Carmela
通讯作者：
Giglione, Carmela
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2.6
作者：
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11.5
作者：
Jones, LW;Eves, ND;Mackey, JR
通讯作者：
Mackey, JR
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Eisenhaber, F;Eisenhaber, B;Wildpaner, M
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Wildpaner, M
影响因子：
5.2
作者：
Ducker, CE;Upson, JJ;Smith, CD
通讯作者：
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