Dopamine receptor D1 agonist inhibits glioblastoma via calpain‑mediated ER stress and mitochondrial dysfunction

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cellular Biology

Background:

• Dopamine receptors play critical roles in glioblastoma (GBM) development and progression.
• Understanding the precise mechanisms of dopamine receptor action is crucial for targeted therapies.

Purpose of the Study:

• To investigate the anti-cancer effects of dopamine receptor D1 agonist SKF83959 on glioblastoma cells.
• To elucidate the molecular pathways involved in SKF83959-induced glioblastoma cell death.

Main Methods:

• Flow cytometry for apoptosis analysis.
• Intracellular calcium and oxidative stress measurements.
• Mitochondrial membrane potential assays, western blotting, and calpain activity assessment.
• In vivo efficacy studies using glioblastoma xenograft models.

Main Results:

• SKF83959 treatment significantly induced apoptotic cell death in glioblastoma cells.
• Increased intracellular calcium and oxidative stress via the PLC/IP3 pathway were observed.
• Mitochondrial dysfunction and endoplasmic reticulum stress were triggered, leading to apoptosis.
• Calpain inhibition by calpastatin ameliorated SKF83959-induced mitochondrial injury and apoptosis.
• SKF83959 demonstrated in vivo anti-tumor efficacy, with increased calpain expression in xenograft tissues.

Conclusions:

• Dopamine D1 agonist SKF83959 exhibits significant anti-cancer effects against glioblastoma.
• The mechanism involves calcium dysregulation, oxidative stress, mitochondrial dysfunction, and ER stress, mediated by calpain activation.
• Calpain activity regulation presents a potential therapeutic strategy for glioblastoma.