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Published on: February 16, 2015
Targeting C5AR1 disrupts complement-driven G0-phase maintenance and overcomes metabolic drug resistance in glioma
1Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Background:
Glioblastoma (GBM) relapse and drug resistance are driven by a subset of quiescent, therapy-tolerant cells that persist in the G0 phase. However, the molecular mechanism coupling immune signaling to tumor cell quiescence and metabolic adaptation remains unclear.
Methods:
Multi-omics analyses of TCGA, CGGA, and GEO datasets, combined with single-cell transcriptomics and in vitro/in vivo experiments, were used to identify complement-related regulators of G0 maintenance. Genetic manipulation (shRNA/overexpression), pharmacological inhibition (C5AR1 antagonist JPE1375; STAT3 inhibitor Stattic), and rescue experiments with recombinant C3 were performed in glioma cell lines and xenograft models. Cell-cycle, mitochondrial, and redox states were assessed by flow cytometry, immunofluorescence, MitoTracker/MitoSOX staining, and ELISA.
Results:
C5AR1 expression was markedly upregulated in GBM and correlated with poor prognosis (HR = 2.7, p = 6.4 × 10-14). Single-cell and functional analyses revealed that C5AR1, activated by complement C3, sustains a spontaneous G0 population through JAK2/STAT3/STAT5 signaling. This axis enhanced mitochondrial integrity and oxidative phosphorylation, maintained low ROS homeostasis, and preserved stem-like features conferring chemoresistance. Knockdown or pharmacological blockade of C5AR1 disrupted G0-phase maintenance, decreased mitochondrial activity, and suppressed tumor growth in xenografts. C5AR1 inhibition also sensitized glioma cells to metabolic drugs by reversing rosiglitazone resistance and enhancing metformin efficacy.
Conclusions:
C5AR1 links extracellular complement activation to intracellular G0-phase maintenance and metabolic resilience in glioma. Targeting the C3-C5-C5AR1 axis disrupts quiescence-driven drug tolerance and represents a promising therapeutic strategy for overcoming chemoresistance in GBM.
Insights
Complement C5a receptor 1 (C5AR1) links immune signaling to glioblastoma cell dormancy and drug resistance. Inhibiting C5AR1 disrupts this axis, offering a new therapeutic strategy for glioblastoma.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Glioblastoma (GBM) recurrence is driven by quiescent, therapy-tolerant cells in G0 phase.
- The molecular mechanisms connecting immune signaling, G0 quiescence, and metabolic adaptation in GBM are not well understood.
Purpose of the Study:
- To investigate the role of complement signaling in maintaining G0 quiescence and chemoresistance in glioblastoma.
- To identify molecular targets for overcoming drug resistance in GBM.
Main Methods:
- Multi-omics and single-cell transcriptomics analyses of GBM datasets.
- In vitro and in vivo experiments using genetic manipulation and pharmacological inhibitors (C5AR1 antagonist JPE1375, STAT3 inhibitor Stattic).
- Assessment of cell-cycle, mitochondrial, and redox states.
Main Results:
- C5AR1 expression is upregulated in GBM and correlates with poor prognosis.
- Complement C3 activates C5AR1, sustaining G0 phase via JAK2/STAT3/STAT5 signaling, enhancing mitochondrial function, and promoting chemoresistance.
- C5AR1 inhibition reduces G0 maintenance, suppresses tumor growth, and sensitizes glioma cells to metabolic drugs.
Conclusions:
- C5AR1 bridges extracellular complement activation and intracellular G0 maintenance, conferring metabolic resilience in glioma.
- Targeting the C3-C5-C5AR1 pathway disrupts quiescence-driven drug tolerance and offers a promising therapeutic strategy for GBM.
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