Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway

Journal of Translational Medicine

Research

Guowei Liu¹  Bin Huang¹  Xuemeng Liu¹  Anjing Chen¹  Zhiyi Xue¹  Yaotian Hu¹  Xun Zhang¹  Xingang Li¹  Xiaofei Liu¹  Jian Wang²  Ning Yang³  Muzi Wen⁴ 

[1] Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, 250012, Jinan, China;Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, 250117, Jinan, China;Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, 250012, Jinan, China;Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, 250117, Jinan, China;Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009, Bergen, Norway;Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong University, 250012, Jinan, China;Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, 250117, Jinan, China;Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, 250012, Jinan, China;School of Public Health, Southern Medical University, 528000, Foushan, China;

关键词: Valtrate;    Glioblastoma;    Mitochondrial apoptosis;    Epithelial mesenchymal transition;    Invasion and migration;    PDGFRA;    MEK;    ERK signaling pathway;   

DOI  :  10.1186/s12967-023-03984-0

 received in 2022-09-23, accepted in 2023-02-13,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundValtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated.MethodsGBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect.ResultsValtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls.ConclusionsTaken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.

【 授权许可】

CC BY   
© The Author(s) 2023

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