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  2. Ciwujianoside E inhibits Burkitt lymphoma cell proliferation and invasion by blocking ENO1-plasminogen interaction and TGF-β1 activation

Ciwujianoside E inhibits Burkitt lymphoma cell proliferation and invasion by blocking ENO1-plasminogen interaction and TGF-β1 activation

  • Biomed Pharmacother. 2024 Jun 18:177:116970. doi: 10.1016/j.biopha.2024.116970.
Haina Wang 1 Shanshan Zhang 2 Xiangjie Kui 3 Jinhong Ren 4 Xuehong Zhang 5 Wenjuan Gao 2 Yinggang Zhang 2 Hongchen Liu 1 Jingyu Yan 6 Mingzhong Sun 7 Sijin Wu 8 Chaoran Wang 9 Jinsong Yan 10
Affiliations

Affiliations

  • 1 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China.
  • 2 Department of Biotechnology & Liaoning Key Laboratory of Cancer Stem Cell Research, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
  • 3 Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China.
  • 4 Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, College of Traditional Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Taiyuan, China.
  • 5 Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 6 CAS Key Laboratory of Separation Science for Analytical Chemistry, Chinese Academy of Sciences, Dalian Institute of Chemical Physics, China.
  • 7 Department of Biotechnology & Liaoning Key Laboratory of Cancer Stem Cell Research, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China. Electronic address: smzlsq@163.com.
  • 8 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, China. Electronic address: sijin_wu@foxmail.com.
  • 9 CAS Key Laboratory of Separation Science for Analytical Chemistry, Chinese Academy of Sciences, Dalian Institute of Chemical Physics, China. Electronic address: wcrpj_505@dicp.ac.cn.
  • 10 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian 116027, China; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Blood Stem Cell Transplantation Institute, Dalian Key Laboratory of hematology, Diamond Bay Institute of Hematology, the Second Hospital of Dalian Medical University, Dalian 116027, China; Department of Pediatric, Pediatric Oncology and Hematology Center, the Second Hospital of Dalian Medical University, Dalian 116027, China. Electronic address: yanjsdmu@dmu.edu.cn.
Abstract

Burkitt's lymphoma (BL) is a rare and highly aggressive B-cell non-Hodgkin lymphoma. Although the outcomes of patients with BL have greatly improved, options for patients with relapsed and refractory BL are limited. Therefore, there is an urgent need to improve BL therapeutics and to develop novel drugs with reduced toxicity. In this study, we demonstrated that Enolase 1 (ENO1) is a potential novel drug target for BL treatment. We determined that ENO1 was aberrantly upregulated in BL, which was closely related to its invasiveness and poor clinical outcomes. Furthermore, using RNA interference, we demonstrated that ENO1 depletion significantly inhibited cell proliferation and invasion both in vitro and in vivo. Mechanistically, we established that ENO1 knockdown suppressed the PI3K-AKT and epithelial-mesenchymal transition (EMT) signaling pathways by reducing plasminogen (PLG) recruitment, plasmin (PL) generation, and TGF-β1 activation. Addition of activated TGF-β1 protein to the culture medium of shENO1 cells reversed the inhibitory effects on cell proliferation and invasion, as well as those on the PI3K-AKT and EMT signaling pathways. Notably, our research led to the discovery of a novel ENO1-PLG interaction inhibitor, Ciwujianoside E (L-06). L-06 effectively disrupts the interaction between ENO1 and PLG, consequently reducing PL generation and suppressing TGF-β1 activation. In both in vitro and in vivo experiments, L-06 exerted impressive antitumor effects. In summary, our study elucidated the critical role of ENO1 in BL cell proliferation and invasion and introduced a novel ENO1 inhibitor, which holds promise for improving the treatment of patients with BL in the future.

Keywords

Burkitt lymphoma; Ciwujianoside E; ENO1; Plasminogen; TGF-β1.

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