Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A

作者全名：Yu, Lu-Rong; Han, Xian-Zhong; Tang, Ying-Zi; Liu, Dan; Luo, Xian-Qin; Qiu, Xue-Wen; Feng, Jie; Yuan, Wen-Xiao; Ding, Jia-Yu

作者地址：[Yu, Lu-Rong; Luo, Xian-Qin] Chongqing Med Univ, Coll Tradit Chinese Med, Chongqing 401331, Peoples R China; [Han, Xian-Zhong; Liu, Dan; Qiu, Xue-Wen; Feng, Jie; Yuan, Wen-Xiao; Ding, Jia-Yu] Chongqing Univ, Chongqing Gen Hosp, Dept Pharm, Chongqing 400014, Peoples R China; [Tang, Ying-Zi] Chongqing Univ, Chongqing Gen Hosp, Dept Pathol, Chongqing 400014, Peoples R China

通信作者：Han, XZ (通讯作者)，Chongqing Univ, Chongqing Gen Hosp, Dept Pharm, Chongqing 400014, Peoples R China.; Tang, YZ (通讯作者)，Chongqing Univ, Chongqing Gen Hosp, Dept Pathol, Chongqing 400014, Peoples R China.

来源：FRONTIERS IN BIOSCIENCE-LANDMARK

ESI学科分类：　

WOS号：WOS:001222942200006

JCR分区：Q2

影响因子：3.3

年份：2024

卷号：29

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：nasopharyngeal carcinoma; silvestrol; apoptosis; ERK1/2; RAP1A; HK2; GADD45A

摘要：Background: Nasopharyngeal carcinoma (NPC) isa malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. Methods: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2 '-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. Results: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. Conclusions: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

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