Mechanism of SC targeting RhoA regulation and its potential value in gastric cancer therapy

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemistry and Biophysics Reports Pub Date : 2025-07-24 DOI:10.1016/j.bbrep.2025.102158

Haixiu Ma , Ping Jiang , Ronghua Ma , Jing Zhao , Qi Wang , Yonghua Xing , Chengzhu Cao , Zhanhai Su

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引用次数: 0

Abstract

RhoA drives the malignant progression of gastric cancer through cytoskeletal remodeling and the regulation of epithelial-mesenchymal transition (EMT). Here, we identified a novel small-molecule inhibitor, (E)-1,9-bis(3,4-dihydroxyphenyl)non-3-en-5-one (SC), targeting RhoA through molecular docking and surface plasmon resonance (SPR) validation. SPR kinetics revealed high-affinity binding (KD = 1.588 μM) with rapid association (ka = 2.769 × 10³ 1/Ms) and slow dissociation (kd = 4.398 × 10⁻³ 1/s), achieving stable SC-RhoA complex formation. In vitro, SC suppressed RhoA expression, in turn upregulating E-cadherin, downregulating N-cadherin and Vimentin, and inhibiting cell migration (p < 0.001). Scanning electron microscopy confirmed pseudopodia retraction and cytoskeletal collapse. Remarkably, oral administration of SC (50 mg/kg/day) attenuated tumor growth in a xenograft model. These results present SC as a potential dual-action RhoA inhibitor that concurrently disrupts GTPase activity and protein stability, offering a promising therapeutic strategy against gastric cancer.

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SC靶向RhoA调控的机制及其在胃癌治疗中的潜在价值

RhoA通过细胞骨架重塑和上皮间质转化（epithelial-mesenchymal transition， EMT）调控推动胃癌的恶性进展。在这里，我们通过分子对接和表面等离子体共振（SPR）验证，鉴定了一种新的小分子抑制剂(E)-1,9-bis（3,4-二羟基苯基）non-3-en-5-one (SC)，靶向RhoA。SPR动力学显示高亲和结合（KD = 1.588 μM），快速结合（ka = 2.769 × 103 1/Ms），缓慢解离（KD = 4.398 × 10−31 /s），形成稳定的SC-RhoA复合物。体外，SC抑制RhoA表达，进而上调E-cadherin，下调N-cadherin和Vimentin，抑制细胞迁移(p <；0.001)。扫描电镜证实假足缩回和细胞骨架塌陷。值得注意的是，口服SC （50 mg/kg/天）可以减轻异种移植模型中的肿瘤生长。这些结果表明SC是一种潜在的双作用RhoA抑制剂，同时破坏GTPase活性和蛋白质稳定性，为胃癌提供了一种有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics

CiteScore

4.60

自引率

0.00%

发文量

191

审稿时长

59 days

期刊介绍： Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.