TAF1 inhibitor Bay-299 induces cell death in acute myeloid leukemia.
TAF1 inhibitor Bay-299 induces cell death in acute myeloid leukemia.
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TAF1抑制剂BAY-299诱导急性髓样白血病的细胞死亡。
DOI：
10.21037/tcr-21-2295
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发表时间：
2021-12
影响因子：
0.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Zhou L;Yao Q;Ma L;Li H;Chen J
急性髓系白血病（acute myeloid leukemia，AML）是最常见的造血系统恶性肿瘤之一。目前AML的强化化疗治愈率仅为40%或更低，迫切需要开发新的有效治疗靶点或药物。TATA盒结合蛋白相关因子1（TAF 1）在转录调控和白血病发生中起重要作用。然而，TAF 1作为AML治疗靶点的潜力仍不清楚。本研究探讨TAF 1抑制剂Bay-299对AML细胞的作用及其分子机制。使用癌症基因组图谱（TCGA）和UALCAN数据库分析TAF 1在各种类型肿瘤中的表达。使用细胞计数试剂盒-8（CCK-8）测定法评价Bay-299对细胞增殖的影响。使用流式细胞术检测细胞死亡、EdU掺入和细胞分化。Western印迹分析用于确认凋亡途径的激活。通过定量实时聚合酶链反应（qRT-PCR）分析细胞周期和细胞死亡相关基因的表达。对公共数据库的分析表明，TAF 1表达在多种类型的肿瘤中升高。用TAF 1抑制剂Bay-299处理AML细胞导致细胞生长的显著抑制、细胞死亡增加、Edu掺入减少和细胞分化增加。凋亡抑制剂Z-VAD和受体相互作用蛋白激酶1（RIPK 1）抑制剂Nec-2可以挽救Bay-299诱导的细胞死亡。Bay-299处理增加了关键促凋亡蛋白的切割，并且这种作用通过施用Z-VAD和Nec-2而改善。此外，Bay-299治疗与细胞周期抑制基因和多种促细胞凋亡基因的表达增加相关，有助于在AML细胞系中观察到的表型。TAF 1抑制剂Bay-299通过多种机制诱导AML细胞死亡，可能是治疗AML患者的有希望的候选药物。
Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies. The cure rate of currently intensive chemotherapy in AML was only 40% or less, and there is an urgent need to develop novel effective therapeutic targets or drugs. The TATA-box binding protein associated factor 1 (TAF1) plays important roles in transcriptional regulation and leukemogenesis. However, the potential of TAF1 as a therapeutic target for AML remains unclear. The present study examined the effects of the TAF1 inhibitor Bay-299 on AML cells and the underlying molecular mechanisms. The expression of TAF1 in various types of tumors was analyzed using The Cancer Genome Atlas (TCGA) and the UALCAN database. The effects of Bay-299 on cell proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Cell death, EdU incorporation, and cell differentiation were detected using flow cytometry. Western blot analysis was utilized to confirm the activation of the apoptotic pathway. Expression of cell cycle and cell death-related genes was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Analysis of the public databases showed that TAF1 expression was elevated in multiple types of tumors. Treatment of AML cells with the TAF1 inhibitor Bay-299 resulted in a remarkable inhibition of cell growth, increased cell death, reduced Edu incorporation, and increased cell differentiation. The apoptosis inhibitor Z-VAD and the receptor-interacting protein kinase 1 (RIPK1) inhibitor Nec-2 could rescue cell death induced by Bay-299. Bay-299 treatment increased the cleavage of key pro-apoptotic proteins, and this effect was ameliorated by administration of Z-VAD and Nec-2. Moreover, Bay-299 treatment was associated with increased expression of cell cycle inhibitor genes and multiple pyroptosis-promoting genes, contributing to the phenotypes observed in AML cell lines. The TAF1 inhibitor Bay-299 induced AML cell death through multiple mechanisms and may be a promising candidate for the treatment of patients with AML.
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影响因子：
64.8
作者：
Wang, Yupeng;Gao, Wenqing;Shao, Feng
通讯作者：
Shao, Feng
影响因子：
16.6
作者：
Wu, Qin;Heidenreich, David;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
12.8
作者：
Estey, Elihu H.
通讯作者：
Estey, Elihu H.
影响因子：
7.3
作者：
Bouché L;Christ CD;Siegel S;Fernández-Montalván AE;Holton SJ;Fedorov O;Ter Laak A;Sugawara T;Stöckigt D;Tallant C;Bennett J;Monteiro O;Díaz-Sáez L;Siejka P;Meier J;Pütter V;Weiske J;Müller S;Huber KVM;Hartung IV;Haendler B
通讯作者：
Haendler B
影响因子：
--
作者：
Tavassoli, Peyman;Wafa, Latif A.;Rennie, Paul S.
通讯作者：
Rennie, Paul S.