China Journal of Oral and Maxillofacial Surgery ›› 2022, Vol. 20 ›› Issue (4): 347-353.doi: 10.19438/j.cjoms.2022.04.006

• Original Articles • Previous Articles     Next Articles

YAP targeting collaboratively enhanced the inhibition effects of selumetinib to neurofibroma-Schwann cells in vitro

YOU Yuan-he, TIAN Zhuo-wei, DU Zhong, XIAO Meng, XU Gui-song, ZHENG Jia-wei, WANG Yan-an   

  1. Department of Oromaxillofacial Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology. Shanghai 200011, China
  • Received:2022-01-21 Revised:2022-04-16 Online:2022-07-20 Published:2022-08-02

Abstract: PURPOSE: To explore the functional status of YAP under selumetinib treatment, and to assess the efficacy of dual targeting YAP and MEK1/2 in inhibition of NF1-Schwann cells in vitro. METHODS: NF1-Schwann cell model was established by lentivirus transfection. RT-PCR and Western blotting were performed to identify the efficacy of gene knockdown. RT-PCR, Western blotting combined with immunofluorescence were carried out to detect the functional status of YAP. siRNA was adopted to knockdown YAP gene expression. CCK-8 was used to evaluate cell viability of Schwann cells under treatment of different drug combination (YAP inhibitor veteporfin and MEK1/2 inhibitor selumetinib). Colony and sphere formation were used to detect the ability of tumor formation in vitro. Combined index analysis was performed to predict the synergistic effect via Chou-Talalay method. GraphPad Prism 8 software package was used for data analysis. RESULTS: Herein, we established a NF1-neurofibroma Schwann cell model(shNf1-RSC96). Increased nuclear translocation and transcriptional activation of YAP were confirmed under selumetinib intervening. Genetic inhibition of YAP significantly enhanced the cytotoxicity of selumetinib to NF1-Schwann cells in vitro. Additionally, combined treatment with Verteporfin and selumetinib showed a synergistic effect in vitro. CONCLUSIONS: Blocking the nuclear translocation and transcriptional activation of YAP enhances inhibition effect of selumetinib to neurofibroma-Schwann cells. Dual targeting of YAP and MEK1/2 might be a promising therapeutic strategy for treating NF1-neurofibroma.

Key words: Neurofibromatosis type 1, YAP, Schwann cell, Target therapy, MEK inhibitor

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