Kappa opioid receptor internalisation-induced p38 nuclear translocation suppresses glioma progression.
Summary
Across molecular to in vivo models, higher KOR expression correlated with better glioma prognosis; KOR overexpression suppressed GBM growth and prolonged survival via binding cytoplasmic p38 and promoting its nuclear translocation. The KOR agonist TRK-820 triggered receptor internalization, activated p38 signaling, and reduced glioma cell viability, supporting KOR agonists as potential adjuvants.
Key Findings
- Higher tumor KOR expression correlated with better glioma patient prognosis.
- KOR overexpression induced GBM cell cycle arrest and apoptosis; knockdown accelerated growth.
- Internalized KOR bound cytoplasmic p38, promoting its nuclear translocation and phosphorylation.
- TRK-820 (selective KOR agonist) induced KOR internalization, activated p38 signaling, and reduced glioma cell viability in vitro.
- KOR overexpression inhibited tumor growth and prolonged survival in orthotopic mouse models.
Clinical Implications
Perioperative selection of opioidergic agents may influence glioma biology. KOR agonists (e.g., nalfurafine/TRK-820) merit translational trials as adjuncts to standard care.
Why It Matters
Reveals a novel KOR–p38 nuclear signaling mechanism suppressing glioma and identifies a clinically available KOR agonist (TRK-820) as a testable adjuvant strategy.
Limitations
- Preclinical study; human clinical efficacy and safety are untested
- Potential off-target and systemic effects of KOR agonism require careful evaluation
Future Directions
Translational trials assessing KOR agonists as adjuvants in glioma and biomarker-driven studies stratifying by tumor KOR expression.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical experimental evidence (in vitro and in vivo models) without human clinical outcomes.
- Study Design
- OTHER