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NSC348884 的细胞毒性不是通过抑制核仁磷酸蛋白寡聚化来介导的。

NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization.

机构信息

Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20, Prague 2, Czech Republic.

Faculty of Mathematics and Physics, Institute of Physics, Charles University, Ke Karlovu 5, 121 16, Prague 2, Czech Republic.

出版信息

Sci Rep. 2021 Jan 13;11(1):1084. doi: 10.1038/s41598-020-80224-1.

DOI:10.1038/s41598-020-80224-1
PMID:33441774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7806638/
Abstract

Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly altered. Dissociation of NPM heterooligomers may thus restore the proper localization and function of wild-type NPM. NSC348884 is supposed to act as a potent inhibitor of NPM oligomerization. The effect of NSC348884 on the NPM oligomerization was thoroughly examined by fluorescence lifetime imaging with utilization of FRET and by a set of immunoprecipitation and electrophoretic methods. Leukemia-derived cell lines and primary AML cells as well as cells transfected with fluorescently labeled NPM forms were investigated. Our results clearly demonstrate that NSC348884 does not inhibit formation of NPM oligomers neither in vivo nor in vitro. Instead, we document that NSC348884 cytotoxicity is rather associated with modified cell adhesion signaling. The cytotoxic mechanism of NSC348884 has therefore to be reconsidered.

摘要

核仁磷酸蛋白（Nucleophosmin，NPM）的突变使其从核仁输出到细胞质中，这在急性髓系白血病（acute myeloid leukemia，AML）中很常见。由于野生型 NPM 与 AML 相关突变体的异源寡聚化，野生型 NPM 会从核仁错位，其功能会发生显著改变。因此，NPM 异源寡聚体的解离可能会恢复野生型 NPM 的正确定位和功能。NSC348884 被认为是一种有效的 NPM 寡聚化抑制剂。本研究通过利用荧光寿命成像和一系列免疫沉淀和电泳方法，深入研究了 NSC348884 对 NPM 寡聚化的影响。研究了白血病衍生的细胞系和原代 AML 细胞以及转染荧光标记 NPM 形式的细胞。我们的结果清楚地表明，NSC348884 既不能在体内也不能在体外抑制 NPM 寡聚体的形成。相反，我们证明 NSC348884 的细胞毒性与其改变的细胞黏附信号转导有关。因此，必须重新考虑 NSC348884 的细胞毒性机制。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/935b/7806638/905bb8270e10/41598_2020_80224_Fig14_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/935b/7806638/8bbf613295b4/41598_2020_80224_Fig1_HTML.jpg
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