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S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma

BACKGROUND: Osteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and conseque...

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Autores principales: Shen, Yifei, Zhao, Shujie, Wang, Shenyu, Pan, Xiaohui, Zhang, Yunkun, Xu, Jingwen, Jiang, Yuqing, Li, Haibo, Zhang, Qiang, Gao, Jianbo, Yang, Qin, Zhou, Yang, Jiang, Shuheng, Yang, Huilin, Zhang, Zhigang, Zhang, Rong, Li, Jun, Zhou, Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412077/
https://www.ncbi.nlm.nih.gov/pubmed/30587459
http://dx.doi.org/10.1016/j.ebiom.2018.12.038
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author Shen, Yifei
Zhao, Shujie
Wang, Shenyu
Pan, Xiaohui
Zhang, Yunkun
Xu, Jingwen
Jiang, Yuqing
Li, Haibo
Zhang, Qiang
Gao, Jianbo
Yang, Qin
Zhou, Yang
Jiang, Shuheng
Yang, Huilin
Zhang, Zhigang
Zhang, Rong
Li, Jun
Zhou, Dong
author_facet Shen, Yifei
Zhao, Shujie
Wang, Shenyu
Pan, Xiaohui
Zhang, Yunkun
Xu, Jingwen
Jiang, Yuqing
Li, Haibo
Zhang, Qiang
Gao, Jianbo
Yang, Qin
Zhou, Yang
Jiang, Shuheng
Yang, Huilin
Zhang, Zhigang
Zhang, Rong
Li, Jun
Zhou, Dong
author_sort Shen, Yifei
collection PubMed
description BACKGROUND: Osteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and consequently hold the significant promise for tumor imaging and targeted therapy. We aimed to explore the biological functions of Sphingosine 1-phosphate receptor 3 (S1PR3), one of the members of GPCRs family, in OS and the possibility of S1PR3 as an effective target for the treatment of osteosarcoma. METHODS: The quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Cell counting kit-8 (CCK8), colony formation assay and cell apoptosis assay were performed to test the cellular proliferation in vitro. Subcutaneous xenograft mouse model was generated to evaluate the functions of S1PR3 in vivo. RNA sequencing was used to compare gene expression patterns between S1PR3-knockdown and control MNNG-HOS cells. In addition, metabolic alternations in OS cells were monitored by XF96 metabolic flux analyzer. Co-immunoprecipitation (Co-IP) assay was used to explore the interaction between Yes-associated protein (YAP) and c-MYC. Chromatin immunoprecipitation was used to investigate the binding capability of PGAM1 and YAP or c-MYC. Moreover, the activities of promoter were determined by the luciferase reporter assay. FINDINGS: S1PR3 and its specific ligand Sphingosine 1-phosphate (S1P) were found elevated in OS, and the higher expression of S1PR3 was correlated with the poor survival rate. Moreover, our study has proved that the S1P/S1PR3 axis play roles in proliferation promotion, apoptosis inhibition, and aerobic glycolysis promotion of osteosarcoma cells. Mechanistically, the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted the nuclear translocation of YAP, which contributed to the formation of the YAP–c-MYC complex and enhanced transcription of the important glycolysis enzyme PGAM1. Moreover, the S1PR3 antagonist TY52156 exhibited in vitro and in vivo synergistic inhibitory effects with methotrexate on OS cell growth. INTERPRETATION: Our study unveiled a role of S1P, a bioactive phospholipid, in glucose metabolism reprogram through interaction with its receptor S1PR3. Targeting S1P/S1PR3 axis might serve as a potential therapeutic target for patients with OS. FUND: This research was supported by National Natural Science Foundation of China (81472445 and 81672587).
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spelling pubmed-64120772019-03-21 S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma Shen, Yifei Zhao, Shujie Wang, Shenyu Pan, Xiaohui Zhang, Yunkun Xu, Jingwen Jiang, Yuqing Li, Haibo Zhang, Qiang Gao, Jianbo Yang, Qin Zhou, Yang Jiang, Shuheng Yang, Huilin Zhang, Zhigang Zhang, Rong Li, Jun Zhou, Dong EBioMedicine Research paper BACKGROUND: Osteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and consequently hold the significant promise for tumor imaging and targeted therapy. We aimed to explore the biological functions of Sphingosine 1-phosphate receptor 3 (S1PR3), one of the members of GPCRs family, in OS and the possibility of S1PR3 as an effective target for the treatment of osteosarcoma. METHODS: The quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Cell counting kit-8 (CCK8), colony formation assay and cell apoptosis assay were performed to test the cellular proliferation in vitro. Subcutaneous xenograft mouse model was generated to evaluate the functions of S1PR3 in vivo. RNA sequencing was used to compare gene expression patterns between S1PR3-knockdown and control MNNG-HOS cells. In addition, metabolic alternations in OS cells were monitored by XF96 metabolic flux analyzer. Co-immunoprecipitation (Co-IP) assay was used to explore the interaction between Yes-associated protein (YAP) and c-MYC. Chromatin immunoprecipitation was used to investigate the binding capability of PGAM1 and YAP or c-MYC. Moreover, the activities of promoter were determined by the luciferase reporter assay. FINDINGS: S1PR3 and its specific ligand Sphingosine 1-phosphate (S1P) were found elevated in OS, and the higher expression of S1PR3 was correlated with the poor survival rate. Moreover, our study has proved that the S1P/S1PR3 axis play roles in proliferation promotion, apoptosis inhibition, and aerobic glycolysis promotion of osteosarcoma cells. Mechanistically, the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted the nuclear translocation of YAP, which contributed to the formation of the YAP–c-MYC complex and enhanced transcription of the important glycolysis enzyme PGAM1. Moreover, the S1PR3 antagonist TY52156 exhibited in vitro and in vivo synergistic inhibitory effects with methotrexate on OS cell growth. INTERPRETATION: Our study unveiled a role of S1P, a bioactive phospholipid, in glucose metabolism reprogram through interaction with its receptor S1PR3. Targeting S1P/S1PR3 axis might serve as a potential therapeutic target for patients with OS. FUND: This research was supported by National Natural Science Foundation of China (81472445 and 81672587). Elsevier 2018-12-23 /pmc/articles/PMC6412077/ /pubmed/30587459 http://dx.doi.org/10.1016/j.ebiom.2018.12.038 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Shen, Yifei
Zhao, Shujie
Wang, Shenyu
Pan, Xiaohui
Zhang, Yunkun
Xu, Jingwen
Jiang, Yuqing
Li, Haibo
Zhang, Qiang
Gao, Jianbo
Yang, Qin
Zhou, Yang
Jiang, Shuheng
Yang, Huilin
Zhang, Zhigang
Zhang, Rong
Li, Jun
Zhou, Dong
S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title_full S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title_fullStr S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title_full_unstemmed S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title_short S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma
title_sort s1p/s1pr3 axis promotes aerobic glycolysis by yap/c-myc/pgam1 axis in osteosarcoma
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412077/
https://www.ncbi.nlm.nih.gov/pubmed/30587459
http://dx.doi.org/10.1016/j.ebiom.2018.12.038
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