Glioblastoma(GBM)is the most challenging malignant tumor of the central nervous system because of its high morbidity,mortality,and recurrence rate.Currently,mechanisms of GBM are still un-clear and there is no effective drug for GBM in the clinic.Therefore,it is urgent to identify new drug targets and corresponding drugs for GBM.In this study,in silico analyses and experimental data show that sphingosine kinase 1(SPHK1)is up-regulated in GBM patients,and is strongly correlated with poor prognosis and reduced overall survival.Overexpression of SPHK1 promoted the proliferation,invasion,metastasis,and clonogenicity of GBM cells,while silencing SPHK1 had the opposite effect.SPHK1 pro-moted inflammation through the NF-κB/IL-6/STAT3 signaling pathway and led to the phosphorylation of JNK,activating the JNK-JUN and JNK-ATF3 pathways and promoting inflammation and proliferation of GBM cells by transcriptional activation of PTX3.SPHK1 interacted with PTX3 and formed a positive feedback loop to reciprocally increase expression,promote inflammation and GBM growth.Inhibition of SPHK1 by the inhibitor,PF543,also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models.In summary,we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM,which may provide opportunities for SPHK1-targeted therapy.

Wan Li;Hongqing Cai;Liwen Ren;Yihui Yang;Hong Yang;Jinyi Liu;Sha Li;Yizhi Zhang;Xiangjin Zheng;Wei Tan;Guanhua Du;Jinhua Wang

The State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Beijing 100050,China;Key Laboratory of Drug Target Research and Drug Screen,Institute of Materia Medica,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100050,China;Department of Neurosurgery,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;State Key Laboratory of Molecular Oncology,Center for Cancer Precision Medicine,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;School of Pharmacy,Xinjiang Medical University,Urumqi 830011,China;Xinjiang Institute of Materia Medica,Urumqi 830004,China

药学学报（英文版）

[1]Wan Li;Hongqing Cai;Liwen Ren;Yihui Yang;Hong Yang;Jinyi Liu;Sha Li;Yizhi Zhang;Xiangjin Zheng;Wei Tan;Guanhua Du;Jinhua Wang-.Sphingosine kinase 1 promotes growth of glioblastoma by increasing inflammation mediated by the NF-κB/IL-6/STAT3 and JNK/PTX3 pathways)[J].药学学报（英文版）,2022(12):4390-4406

clonogenicity,PF543

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