Endoplasmic Reticulum Stress Contributed to Dipyridamole-Induced Impaired Autophagic Flux and Glioma Apoptosis

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cellular Biology

Background:

• Elevated intracellular cyclic adenosine monophosphate (cAMP) levels inhibit glioma cell proliferation, differentiation, and apoptosis.
• Phosphodiesterase inhibition is a key strategy to increase intracellular cAMP levels.

Purpose of the Study:

• To investigate the anti-glioma potential of dipyridamole, a phosphodiesterase inhibitor.
• To elucidate the molecular mechanisms underlying dipyridamole's effects on glioma cells.

Main Methods:

• Treatment of human U87 and T98G glioma cells with dipyridamole.
• Assessment of cell viability, clonogenic colonization, migration, and invasion.
• Analysis of Noxa expression, Endoplasmic Reticulum (ER) stress, autophagic flux, and Yes-associated Protein 1 (YAP1) phosphorylation and reduction.
• Pharmacological and genetic studies to confirm apoptosis pathways.

Main Results:

• Dipyridamole treatment reduced glioma cell viability, proliferation, migration, and invasion.
• Dipyridamole induced Noxa upregulation, ER stress, impaired autophagic flux, and YAP1 phosphorylation/reduction.
• The drug initiated Noxa-guided apoptosis via ER stress and inhibited the YAP1/autophagy axis, enhancing glioma cell vulnerability to apoptosis.

Conclusions:

• Dipyridamole exhibits significant anti-glioma effects by promoting apoptosis through ER stress and modulating the YAP1/autophagy pathway.
• The findings highlight dipyridamole as a potential therapeutic agent for glioma, warranting further investigation into its multifaceted anti-cancer mechanisms.