2. Academic Validation
  3. Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance

Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance

  • Nat Commun. 2021 Jun 17;12(1):3720. doi: 10.1038/s41467-021-24108-6.
Haohao Huang  # 1 2 3,  Songyang Zhang  # 1,  Yuanyuan Li  # 1,  Zhaodan Liu 1,  Lanjuan Mi 1,  Yan Cai 1,  Xinzheng Wang 1,  Lishu Chen 1,  Haowen Ran 1,  Dake Xiao 1,  Fangye Li 4,  Jiaqi Wu 1,  Tingting Li 1,  Qiuying Han 1,  Liang Chen 1,  Xin Pan 1,  Huiyan Li 1,  Tao Li 1,  Kun He 1,  Ailing Li 1 5,  Xuemin Zhang 1 5 6,  Tao Zhou 1 2,  Qing Xia 7,  Jianghong Man 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
  • 2 Nanhu Laboratory, Jiaxing, Zhejiang Province, China.
  • 3 Department of Neurosurgery, General Hospital of Central Theater Command of Chinese People's Liberation Army, Wuhan, PR China.
  • 4 Department of Neurosurgery, First Medical Center of PLA General Hospital, Beijing, China.
  • 5 The First Hospital of Jilin University, Changchun, China.
  • 6 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, China.
  • 7 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China. [email protected].
  • 8 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China. [email protected].
  • 9 Nanhu Laboratory, Jiaxing, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 34140524 DOI: 10.1038/s41467-021-24108-6
Abstract

Low levels of Reactive Oxygen Species (ROS) are crucial for maintaining Cancer Stem Cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.

Figures
Products