Amlodipine exerts inhibitory effects against glioma stem cells through degrading EGFR and down-regulating its
Zengyang Li1, Xiaopei Zhang1, Ping Wen1
1Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
Glioblastoma is the most aggressive and lethal primary brain tumor in adults with the poorest prognosis, due to its high therapeutic resistance and rapid recurrence, which is closely associated with glioma stem cells (GSCs), which represent a critical therapeutic target in this refractory malignancy. As a classical calcium channel blocker (CCB), amlodipine exhibits exact anti-tumor effect independent of CCB activity. The present study further investigated its effects on GSCs and elucidated the relevant molecular mechanisms. Our results revealed that amlodipine exerted multifaceted inhibitory effects on GSCs, including reducing cell viability, self-renewal, invasiveness, and stemness, while enhancing apoptosis and suppressing intracranial tumor growth derived from GSCs. In contrast, other dihydropyridine CCBs and calcium chelators did not exhibit comparable anti-GSC effects at equivalent concentrations, suggesting that the anti-GSC activity of amlodipine is independent of calcium channel blockade. Mechanistically, amlodipine demonstrated high binding affinity to EGFR on the plasma membrane of GSCs, triggering its internalization via clathrin-independent lipid raft-mediated endocytosis. This process leaded to the lysosomal degradation of EGFR, resulting in the downregulation of EGFR protein levels and subsequent inhibition of downstream pro-survival signaling pathways. Taken together, our studies suggest that amlodipine suppresses GSCs-initiated tumor development via degrading EGFR and down-regulating its downstream pro-survival pathways, implying that amlodipine has novel potential as a therapeutic agent targeting GSCs in glioblastoma, deserving further investigations.
Insights
Amlodipine effectively targets glioma stem cells (GSCs) in glioblastoma by degrading EGFR, independent of its calcium channel blocking activity. This novel mechanism offers potential for new glioblastoma therapies.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma is an aggressive brain tumor with poor prognosis.
- Glioma stem cells (GSCs) drive glioblastoma's therapeutic resistance and recurrence.
- Targeting GSCs is crucial for effective glioblastoma treatment.
Purpose of the Study:
- To investigate the anti-tumor effects of amlodipine on GSCs.
- To elucidate the molecular mechanisms underlying amlodipine's action on GSCs.
- To explore amlodipine's potential as a GSC-targeted glioblastoma therapy.
Main Methods:
- Assessed amlodipine's effects on GSC viability, self-renewal, invasiveness, stemness, and apoptosis.
- Investigated amlodipine's impact on intracranial GSC-derived tumor growth.
- Examined the molecular mechanism involving Epidermal Growth Factor Receptor (EGFR) endocytosis and degradation.
Main Results:
- Amlodipine significantly inhibited GSC viability, self-renewal, invasiveness, and stemness, while promoting apoptosis.
- Amlodipine suppressed intracranial tumor growth derived from GSCs.
- Amlodipine induced EGFR internalization and lysosomal degradation, downregulating EGFR signaling pathways.
Conclusions:
- Amlodipine exhibits potent anti-GSC activity independent of its calcium channel blocking function.
- Amlodipine targets GSCs by degrading EGFR and inhibiting downstream pro-survival pathways.
- Amlodipine presents a promising therapeutic strategy for glioblastoma targeting GSCs.
