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β-拉帕醌通过抑制Gal-3/Gal-3BP/IL6轴减弱骨髓间充质干细胞介导的神经母细胞瘤恶性转化。

Beta-Lapachone Attenuates BMSC-Mediated Neuroblastoma Malignant Transformation by Inhibiting Gal-3/Gal-3BP/IL6 Axis.

作者信息

Zhou Yang, Yan Hui, Zhou Qiang, Feng Ruiling, Wang Penggao, Yang Fang, Zhang Yaodong, Yuan Ziqiao, Zhai Bo

机构信息

Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou University, Zhengzhou, China.

Department of Cardiothoracic Surgery, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, China.

出版信息

Front Pharmacol. 2021 Nov 1;12:766909. doi: 10.3389/fphar.2021.766909. eCollection 2021.

DOI:10.3389/fphar.2021.766909
PMID:34790130
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8591123/
Abstract

The inflammatory factor IL6 secreted by bone marrow mesenchymal stem cells (BMSCs) in the tumor microenvironment (TME) facilitates the survival and therapeutic resistance of neuroblastoma (NB). Here, we found that IL6 expression in primary tumor tissues or bone marrow (BM) metastases was closely associated with the disease risk and prognosis of NB patients. IL6 secretion from immortalized BMSC (iBMSC) was directly regulated by NB cells and is involved in promoting the proliferation and metastasis of NB cells. Beta-Lapachone (ARQ-501, LPC), an -naphthoquinone natural product, significantly prevented the iBMSC-induced malignant transformation effect on NB cells through suppressing the expression and secretion of IL6 from iBMSC and . Mechanistically, LPC disrupted the crosstalk between NB cells and iBMSC in an NQO1-dependent manner through blocking the Gal-3/Gal-3BP/IL6 axis. Our results reveal the effect of iBMSC-derived IL6 on TME-induced malignant transformation of NB cells, and provide theoretical basis for the clinical application of LPC as a potential IL6 inhibitor in high-risk refractory NB patients.

摘要

肿瘤微环境（TME）中骨髓间充质干细胞（BMSCs）分泌的炎性因子IL6促进神经母细胞瘤（NB）的存活和治疗抗性。在此，我们发现原发性肿瘤组织或骨髓（BM）转移灶中IL6的表达与NB患者的疾病风险和预后密切相关。永生化BMSC（iBMSC）分泌的IL6受NB细胞直接调控，并参与促进NB细胞的增殖和转移。β-拉帕醌（ARQ-501，LPC），一种萘醌天然产物，通过抑制iBMSC中IL6的表达和分泌，显著阻止了iBMSC诱导的NB细胞恶性转化作用。机制上，LPC通过阻断Gal-3/Gal-3BP/IL6轴，以NQO1依赖的方式破坏了NB细胞与iBMSC之间的串扰。我们的结果揭示了iBMSC衍生的IL6对TME诱导的NB细胞恶性转化的作用，并为LPC作为潜在的IL6抑制剂在高危难治性NB患者中的临床应用提供了理论依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/51d1529ac7c9/fphar-12-766909-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/97cdb2bd14f2/fphar-12-766909-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/4df946974517/fphar-12-766909-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/78cb47301853/fphar-12-766909-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/859377027c04/fphar-12-766909-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/1730350a751a/fphar-12-766909-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/51d1529ac7c9/fphar-12-766909-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/97cdb2bd14f2/fphar-12-766909-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/4df946974517/fphar-12-766909-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/78cb47301853/fphar-12-766909-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/859377027c04/fphar-12-766909-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/1730350a751a/fphar-12-766909-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b794/8591123/51d1529ac7c9/fphar-12-766909-g006.jpg

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