当前位置: X-MOL 学术bioRxiv. Cancer Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Phosphoproteomic Landscape of AML Cells Treated with the ATP-Competitive CK2 Inhibitor CX-4945
bioRxiv - Cancer Biology Pub Date : 2021-01-04 , DOI: 10.1101/2021.01.04.425248
Mauro Rosales , Arielis Rodriguez-Ulloa , Vladimir Besada , Ailyn C. Ramon , George V. Perez , Yassel Ramos , Osmany Guirola , Luis J. Gonzalez , Katharina Zettl , Jacek R. Wisniewski , Yasser Perera , Silvio E. Perea

Casein kinase 2 (CK2) regulates a plethora of proteins with pivotal roles in solid and hematological neoplasia. Particularly, in acute myeloid leukemia (AML) CK2 has been pointed as an attractive therapeutic target and prognostic marker. Here, we explored the impact of CK2 inhibition over the phosphoproteome of two cell lines representing major AML subtypes. Quantitative phosphoproteomic analysis was conducted to evaluate changes in phosphorylation levels after incubation with the ATP-competitive CK2 inhibitor CX-4945. Functional enrichment, network analysis, and database mining were performed to identify biological processes, signaling pathways, and CK2 substrates that are responsive to CX-4945. A total of 273 and 1310 phosphopeptides were found differentially modulated in HL-60 and OCI-AML3 cells, respectively. Despite regulated phosphopeptides belong to proteins involved in multiple biological processes and signaling pathways, most of these perturbations can be explain by direct CK2 inhibition rather than off-target effects. Furthermore, CK2 substrates regulated by CX-4945 are mainly related to mRNA processing, translation, DNA repair, and cell cycle. Overall, we evidenced that CK2 inhibitor CX-4945 impinge on mediators of signaling pathways and biological processes essential for primary AML cells survival and chemosensitivity, reinforcing the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.

中文翻译:

ATP竞争性CK2抑制剂CX-4945处理的AML细胞的磷酸化蛋白质组学景观

酪蛋白激酶2(CK2)调节大量蛋白质,在实体和血液肿瘤中起关键作用。特别地,在急性髓细胞性白血病(AML)中,CK2已被认为是有吸引力的治疗靶标和预后标志物。在这里,我们探讨了CK2抑制对代表主要AML亚型的两种细胞系的磷酸化蛋白质组的影响。与ATP竞争性CK2抑制剂CX-4945孵育后,进行了磷酸化蛋白质组学定量分析,以评估磷酸化水平的变化。进行功能增强,网络分析和数据库挖掘,以识别对CX-4945敏感的生物过程,信号传导途径和CK2底物。分别在HL-60和OCI-AML3细胞中发现总共273和1310个磷酸肽被差异调节。尽管受调节的磷酸肽属于涉及多个生物学过程和信号传导途径的蛋白质,但这些干扰中的大多数可以通过直接CK2抑制而不是脱靶效应来解释。此外,CX-4945调控的CK2底物主要与mRNA加工,翻译,DNA修复和细胞周期有关。总体而言,我们证明了CK2抑制剂CX-4945会影响原发性AML细胞存活和化学敏感性必不可少的信号传导途径和生物学过程的介质,从而增强了针对AML靶向治疗的蛋白激酶CK2的药理学阻断作用的基本原理。CX-4945调控的CK2底物主要与mRNA加工,翻译,DNA修复和细胞周期有关。总体而言,我们证明了CK2抑制剂CX-4945会影响原发性AML细胞存活和化学敏感性必不可少的信号传导途径和生物学过程的介质,从而增强了针对AML靶向治疗的蛋白激酶CK2的药理学阻断作用的基本原理。CX-4945调控的CK2底物主要与mRNA加工,翻译,DNA修复和细胞周期有关。总体而言,我们证明了CK2抑制剂CX-4945会影响原发性AML细胞存活和化学敏感性必不可少的信号传导途径和生物学过程的介质,从而增强了针对AML靶向治疗的蛋白激酶CK2的药理学阻断作用的基本原理。
更新日期:2021-01-05
down
wechat
bug