2. Academic Validation
  3. Oridonin inhibits bladder cancer survival and immune escape by covalently targeting HK1

Oridonin inhibits bladder cancer survival and immune escape by covalently targeting HK1

  • Phytomedicine. 2024 Feb 7:126:155426. doi: 10.1016/j.phymed.2024.155426.
Shuangjie Liu 1,  Xialu Wang 2,  Xiaojie Sun 3,  Baojun Wei 4,  Zhaowei Jiang 4,  Yongze Ouyang 4,  Toshinori Ozaki 5,  Meng Yu 6,  Yongxiang Liu 7,  Rong Zhang 8,  Yuyan Zhu 9
Affiliations

Affiliations

  • 1 Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China; Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, China; Department of Urology, The First Hospital of China Medical University, Shenyang 110001, China.
  • 2 School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, China.
  • 3 School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
  • 4 Department of Urology, The First Hospital of China Medical University, Shenyang 110001, China.
  • 5 Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan.
  • 6 Department of Laboratory Animal Science, China Medical University. Key Laboratory of Transgenetic Animal Research. No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, China.
  • 7 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 8 School of Life Science and Bio-Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China. Electronic address: zhangrong@syphu.edu.cn.
  • 9 Department of Urology, The First Hospital of China Medical University, Shenyang 110001, China. Electronic address: yyzhu@cmu.edu.cn.
PMID: 38367425 DOI: 10.1016/j.phymed.2024.155426
Abstract

Background: Hexokinase I (HK1) is highly expressed in a variety of malignancies, regulates glycolytic pathway in Cancer cells, and thus considered to be one of the promising molecular targets for Cancer therapy. Nonetheless, the development of a specific inhibitor against HK1 remains elusive.

Purpose: This study aims to elucidate the mechanism by which oridonin inhibits the proliferation and immune evasion of bladder Cancer cells, specifically through the suppression of HK1.

Methods: To examine the mechanisms by which oridonin directly binds to cysteines of HK1 and inhibits bladder Cancer growth, this study utilized a variety of methods. These included the Human Proteome Microarray, Streptavidin-agarose affinity assay, Biolayer Interferometry (BLI) ainding analysis, Mass Spectrometry, Cellular Thermal Shift Assay, Extracellular Acidification Rate measurement, and Xenotransplant mouse models.

Results: As indicated by our current findings, oridonin forms a covalent bond with Cys-813, located adjacently to glucose-binding domain of HK1. This suppresses the enzymatic activity of HK1, leading to an effective reduction of glycolysis, which triggers cell death via Apoptosis in cells derived from human bladder Cancer. Significantly, oridonin also inhibits lactate-induced PD-L1 expression in bladder Cancer. Furthermore, pairing oridonin with a PD-L1 inhibitor amplifies the cytotoxicity of CD8+ T cells against bladder Cancer.

Conclusion: This research strongly suggests that oridonin serves as a covalent inhibitor of HK1. Moreover, it indicates that functional cysteine residue of HK1 could operate as viable targets for selective inhibition. Consequently, oridonin exhibits substantial potential for the evolution of anti-cancer agents targeting the potential therapeutic target HK1 via metabolism immunomodulation.

Keywords

Bladder cancer; Glycolysis; Hexokinase I; Immune escape; Oridonin.

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