Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (4): 1135-1152.doi: 10.4103/NRR.NRR-D-23-00875

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Impacts of Nutlin-3a and exercise on murine double minute 2–enriched glioma treatment

Yisheng Chen1, #, Zhongcheng Fan2, #, Zhiwen Luo1, #, Xueran Kang3, #, Renwen Wan1, Fangqi Li1, Weiwei Lin4, Zhihua Han5, Beijie Qi1, Jinrong Lin1, Yaying Sun1, Jiebin Huang6, Yuzhen Xu7, *, Shiyi Chen1, *   

  1. 1Department of Sport Medicine, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Orthopedic Surgery, Hainan Province Clinical Medical Center, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, China; 3Department of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 4Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; 5Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; 6Department of Infectious Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China; 7Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
  • Online:2025-04-15 Published:2024-07-03
  • Contact: Shiyi Chen, MD, PhD, cshiyi@163.com; Yuzhen Xu, PhD, tianyayizhe@126.com.
  • Supported by:
    This work was supported by Project of the Health Shanghai Initiative Special Fund (Medical-Sports Integration, Creating a New Model of Exercise for Health), No. JKSHZX-2022-02 (to SC).

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Abstract: Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role of the small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are the potential anti-cancer effects of SUMOylation. We used machine learning to create the exercise and SUMO-related gene signature (ESLRS). This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers. We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers, specifically highlighting how murine double minute 2 (MDM2), a component of the ESLRS, can be targeted by nutlin-3. This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation. Using comprehensive CRISPR screening, we validated the effects of specific ESLRS genes on low-grade glioma progression. We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation. Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway. Its efficacy decreased with MDM2 overexpression, and this was reversed by Nutlin-3a or exercise. Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation. Notably, both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells. These results suggest the potential for Nutlin-3a, an MDM2 inhibitor, with physical exercise as a therapeutic approach for glioma management. Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise, natural products, and immune regulation in cancer treatment.

Key words: exercise and SUMO-related gene signatures (ESLRS), glioblastoma management, low-grade glioma, natural bioactives, neural regeneration, physical exercise