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sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis

Cellular & Molecular Immunology 2022年第10期19卷 1153-1167页

作者： Poyee Lau Guanxiong Zhang Shuang Zhao Long Liang Hailun Zhang Guowei Zhou Mien-Chie Hung Xiang Chen Hong Liu Department of Dermatology Xiangya HospitalCentral South UniversityChangshaChina National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology ChangshaChina Hunan Key Laboratory of Skin Cancer and Psoriasis ChangshaChina Hunan Engineering Research Center of Skin Health and Disease ChangshaChina Medical Genetics&School of Life Sciences Central South UniversityChangshaHunan410078China Department of Research and Development Beijing GAP Biotechnology Co.LtdBeijing102600China Graduate Institute of Biomedical Sciences Research Center for Cancer Biology and Center for Molecular MedicineChina Medical UniversityTaichungTaiwanChina Department of Biotechnology Asia UniversityTaichungTaiwanChina Department of Molecular and Cellular Oncology the University of Texas MD Anderson Cancer CenterHoustonTXUSA Xiangya Clinical Research Center for Cancer Immunotherapy Central South UniversityChangshaChina

Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.

关键词： sphingosine kinase Programmed cell death ligand 1 Programmed cell death protein 1 Melanoma Tumor microenvironment Immune checkpoint blockade

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KAI1 inhibits HGF-induced invasion of pancreatic cancer by sphingosine kinase activity

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Hepatobiliary & Pancreatic Diseases International 2011年第2期10卷 201-208页

作者： Xu Liu,Xiao-Zhong Guo,Wei-Wei Zhang,Zhuo-Zhuang Lu,Qun-Wei Zhang, Hai-Feng Duan and Li-Sheng Wang State Key Laboratory of Cancer Biology and Institute of Digestive Diseases,Xijing Hospital of Digestive Disease,Fourth Military Medical University,Xi’an 710032,China Department of Gastroenterology,Shenyang General Hospital of PLA,Shenyang 110016, China Department of Experimental Hematology,Beijing Institute of Radiation Medicine,Beijing 100850,China State Key Laboratory of Cancer Biology and Institute of Digestive Diseases Xijing Hospital of Digestive Disease Fourth Military Medical University Xi'an 710032 China Department of Gastroenterology Shenyang General Hospital of PLA Shenyang 110016 China Department of Experimental Hematology Beijing Institute of Radiation Medicine Beijing 100850 China

BACKGROUND:KAI1/CD82 has been reported to attenuate the process of metastases in a variety of tumors;however,its mechanism of action in invasion has not been fully elucidated. The present study aimed to investigate the importance of KAI1 in invasion and its correlation with activation of sphingosine kinase(SPK)in human pancreatic cancer PANC1 and Miapaca-2 cell lines. METHODS:The expression of KAI1 in PANC1 and Miapaca-2 cells,which was mediated by recombinant adenovirus(Ad-KAI1), was assessed by a flow cytometer and Western blotting.After successful infection was established,in vitro growth curve and invasive ability in Boyden Chamber assay were studied.The presence of KAI1 correlating with c-Met and SPK was detected by co-immunoprecipitation and[γ-32P]ATP incorporation. RESULTS:KAI1 genes had no significant effects on the curve representing cell growth.After infection with the KAI1 gene,decreased invasive ability in the Boyden Chamber assay was observed in PANC1 and Miapaca-2 cells that were induced by hepatocyte growth factor.Over-expression of KAI1 in the cells led to the deactivation of SPK and a decreased level of intracellular sphingosine-1-phosphate.No correlation was observed between c-Met and KAI1 during co-immunoprecipitation. CONCLUSION:The results of this study for the first time demonstrated a regulatory role for KAI1 in SPK activation, which leads to decreased invasive ability in disease progression of human pancreatic cancer.

关键词： adenovirus vector KAI1 gene sphingosine kinase pancreatic cancer cell lines

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IGFBP-3 Enhances IGF-II Cell SignaUng through Activation of sphingosine kinase and S1P Production in Human Extravillous Trophoblasts

IGFBP-3 Enhances IGF-II Cell SignaUng through Activation of ...

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“细胞活动生命活力”——中国细胞生物学学会全体会员代...

作者： Andree Gruslin Chronic Disease Program Ottawa Hospital Rcsearch InstituteOttawaONCanada Cellular and Molecular Medicine University of Ottawa Obstetrics and Gynecology The Ottawa HospitalOttawaONCanada

IGF system plays an essential role in placental development and fetal growth.IGFBP-3 forms a complex with IGF-Ⅱthus reducing its bio-availability.In other cell types,however,IGFBP-3 has also been shown to positively regulate IGF cell signaling through up-regulating sphingosine kinase(Sphk).The objective of this study is to examine whether IGFBP-3 enhances IGF-Ⅱcell signaling in human extravillous trophoblasts(EVT) and exploring its underlying mechanism. By using Western blot,Western Ligand Blot analysis,our study shows that human EVT(HTR8/SVneo cells) secrete IGFBPs,including IGFBP-3,and IGF-Ⅱ.Pre-treatment of HTR8/SVneo cells with relatively low concentrations of IGFBP3(0.5 nM,1 h) enhances IGF-Ⅱ(1 nM,10 min)-induced cell signaling as indicated by increases in phosphorylation of AKT and ERK,as well as EVT migration.In contrast,when cells are treated with higher dosages of IGFBP-3(2 nM) and IGF-Ⅱ(1 nM,10 min),IGF-Ⅱcell signaling is inhibited. Co-treatment of IGFBP-3 and sphingosine induces ERK phosphorylation,an effect mediated by sphingosine phosphotate(S1P,the product of Sphk).This effect is attenuated by DMS(Sphk inhibitor). Furthermore,low dose IGFBP-3 treatment for 1 hour increases Sphk protein content and its phosphorylation in the membrane fraction of trophoblasts without affecting its total protein level,indicating IGFBP3 induces Sphk activation.Finally,we also observed that S1P itself enhances IGF-Ⅱ-mediated AKT and ERK phosphorylation as well as IGF-Ⅱ-induced IGF1R phosphorylation,providing evidence that S1P potentiates IGF-Ⅱcell signaling by activating IGF type 1 receptor.In conclusion,at relatively low concentrations,IGFBP3 enhances IGF-Ⅱ-mediated signaling and cell migration by activating Sphk and S1P production in human EVT cell line.This suggests a tight regulation of IGFBP-3 expression is important in the regulation of IGF-Ⅱ-related functions,including trophoblast migration.

关键词： Trophoblast Invasion IGFBP-3 IGF-Ⅱ sphingosine kinase

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sphingosine signaling and atherogenesis

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Acta Pharmacologica Sinica 2004年第7期25卷 3-8页

作者： Jacob HANSEN-SCHWARTZ,Lars EDVINSSON Department of Clinical Experimental Research Glostrup University Hospital Glostrup Denmark Division of Experimental Vascular Research Institute of Medicine Lund University Sweden

sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger toregulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors(GPCRs) named the endothelial differentiation gene (EDG) family. Five closely related GPCRs of EDG family(EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. Thesereceptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration,proliferation, apoptosis, intracellular Ca2+ mobilization, and expression of adhesion molecules. The formation of anatherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothe-lium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S1P signaling may play animportant role in the pathogenesis of atherosclerotic vascular disease. This review highlights S1P signalling invascular cells and its involvement in the formation of atherosclerotic lesions.

关键词： sphingosine 1-phosphate sphingosine kinase sphingosine-1-phosphate receptors endothelium myocardium smooth muscle arteriosclerosis

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Cross-Talk between Extracellular S1P/S1P2 and P42/44 MAPK in bcr/abl Positive Chronic Myeloid Leukemia Cells

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Chinese Journal of Cancer Research 2009年第1期21卷 20-27页

作者： Yin Xu Fei-qun Zheng Qun-wei Zhang Yang Liu Hai-feng Duan Chun-ping Cui Bin Wu Yi-de Qin Deparment of Biochemistry and Molecular Biology Anhui Medical University Hefei 230032 China Department of Experimental Hematology Beijing Institute of Radiation Medicine Beijing 100850 China Key Laboratory of Carcinogenesis and Translational Research （Ministry of Education） Department of lnterventional Therapy Peking University School of Oncology Beijing Cancer Hospital ＆ Institute Beijing 100142 China

Objective： BCR/ABL oncoprotein-expression is associated with uncontrolled cell growth. sphingosine kinase 1 （SPK1） regulates the production of sphingosine 1-phosphate （S1P）, a key lipid signal molecular in cell proliferation and survival. The objective of this study was to elucidate the roles of S1P and its receptors in bcr/abl positive chronic myeloid leukemia （CML） cells. Methods： The expressions of SIP receptors： S1P1, S1P2 and S1P3 in CML cells were detected by RT-PCR. SPK1 expression, activity and extracellular S1P were determined in ECV304 and HL-60 cells which were transfected with bcr/abl gene. To elucidate the relationship between the BCR/ABL, ERK/MAPK （extracellular signal-regulated kinase/mitogen-activated protein kinase）, SPK/S 1P and S 1P/S 1 P2 signal pathways, bcr/abl positive CML cell line K562 was treated with STI571, PD98059, N,N-dimethyl sphingosine （DMS） and JTE-013. Results： Retrovirus-mediated overexpression of bcr/abl gene in ECV304 and HL-60 cells resulted in upregulation of the expression, activity of SPK1 and increase of the secretion of SIP, whereas treatment of STI571 and PD98059 decreased the BCR/ABL-induced S1P secretion. Treatment of DMS reduced S1P secretion and P42/44MAPK phosphorylation. S1P2-selective antagonist JTE-013 could also decrease P42/44MAPK phosphorylation. Conclusion： These results suggest that BCR/ABL up-regulates extracellular sphingosine 1-phosphate through sphingosine kinase 1 and there is cross-talk between SPK1/S1P/S1P2 and P42/44MAPK in bcr/abl positive CML cells.

关键词： sphingosine kinase sphingosine 1-phosphate CML Extracellular signal-regulated kinase/mitogen-activated protein kinase Cross-talk

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