Preclinical Targeting of the PGRMC1-CK2 Axis with Silmitasertib: A Potential Strategy for Lung Adenocarcinoma Therapy.

IF 1.7 Q3 PHARMACOLOGY & PHARMACY Drug Research Pub Date : 2024-04-01 Epub Date: 2024-03-20 DOI:10.1055/a-2273-2389
S Solaipriya, M Anbalagan, V Sivaramakrishnan
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Abstract

Progesterone receptor membrane component 1 (PGRMC1) is a pleiotropic protein over-expressed in lung adenocarcinoma (LUAD). The precise molecular mechanisms underlying the signature motif of Casein kinase (CK2) presence in PGRMC1 and their role in LUAD remain unclear. X-ray crystallographic structure for CK2 and PGRMC1 from the PubChem database was obtained and subjected to protein-protein interaction (PPI) analysis to identify their interactions. In addition, the CK2 inhibitor - Silmitasertib was also utilised to understand the interaction between PGRMC1-CK2. The PPI complex (PGRMC1-CK2) and the PPI-ligand interaction analysis and their Molecular Dynamics (MD) studies revealed the stability of their interactions and critical amino acid contacts within the 5Ǻ vicinity of the CK2 signature motif "T/S-x-x-E/D". Moreover, in-vitro colony formation assay, migration assay, and gene expression analysis using quantitative Real-time PCR revealed that Silmitasertib (IC50-2.5 μM) was highly influential in suppressing the PGRMC1-CK2 expression axis. In conclusion, our study infers that PGRMC1-CK-2 axis inhibition could be a potential therapeutic option to limit the promotion and progression of lung cancer.

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临床前使用 Silmitasertib 靶向 PGRMC1-CK2 轴:肺腺癌治疗的潜在策略。
孕酮受体膜组件 1(PGRMC1)是一种在肺腺癌(LUAD)中过度表达的多向蛋白。酪蛋白激酶(CK2)在 PGRMC1 中的标志性基团及其在 LUAD 中作用的确切分子机制仍不清楚。我们从 PubChem 数据库中获得了 CK2 和 PGRMC1 的 X 射线晶体结构,并对其进行了蛋白质-蛋白质相互作用(PPI)分析,以确定它们之间的相互作用。此外,还利用 CK2 抑制剂 Silmitasertib 来了解 PGRMC1-CK2 之间的相互作用。PPI 复合物(PGRMC1-CK2)和 PPI 配体相互作用分析及其分子动力学(MD)研究揭示了它们之间相互作用的稳定性以及 CK2 标志性图案 "T/S-x-x-E/D "5Ǻ附近的关键氨基酸接触。此外,体外集落形成试验、迁移试验和基因表达定量实时荧光定量 PCR 分析表明,Silmitasertib(IC50-2.5 μM)对抑制 PGRMC1-CK2 表达轴的影响很大。总之,我们的研究推断,PGRMC1-CK-2轴抑制可能是一种潜在的治疗方法,可限制肺癌的发生和发展。
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来源期刊
Drug Research
Drug Research PHARMACOLOGY & PHARMACY-
CiteScore
3.50
自引率
0.00%
发文量
67
期刊介绍: Drug Research (formerly Arzneimittelforschung) is an international peer-reviewed journal with expedited processing times presenting the very latest research results related to novel and established drug molecules and the evaluation of new drug development. A key focus of the publication is translational medicine and the application of biological discoveries in the development of drugs for use in the clinical environment. Articles and experimental data from across the field of drug research address not only the issue of drug discovery, but also the mathematical and statistical methods for evaluating results from industrial investigations and clinical trials. Publishing twelve times a year, Drug Research includes original research articles as well as reviews, commentaries and short communications in the following areas: analytics applied to clinical trials chemistry and biochemistry clinical and experimental pharmacology drug interactions efficacy testing pharmacodynamics pharmacokinetics teratology toxicology.
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