Abstract
Elevation of intracellular cAMP levels has been implicated in glioma cell proliferation inhibition, differentiation, and apoptosis. Inhibition of phosphodiesterase is a way to elevate intracellular cAMP levels. The present study aimed to investigate the anti-glioma potential of dipyridamole, an inhibitor of phosphodiesterase. Upon treatment with dipyridamole, human U87 glioma cells decreased cell viability, clonogenic colonization, migration, and invasion, along with Noxa upregulation, Endoplasmic Reticulum (ER) stress, impaired autophagic flux, Yes-associated Protein 1 (YAP1) phosphorylation, and YAP1 reduction. Pharmacological and genetic studies revealed the ability of dipyridamole to initiate Noxa-guided apoptosis through ER stress. Additionally, the current study further identified the biochemical role of YAP1 in communicating with ER stress and autophagy under situations of dipyridamole treatment. YAP1 promoted autophagy and protected glioma cells from dipyridamole-induced apoptotic cell death. Dipyridamole impaired autophagic flux and rendered glioma cells more vulnerable to apoptotic cell death through ER stress-inhibitable YAP1/autophagy axis. The overall cellular changes caused by dipyridamole appeared to ensure a successful completion of apoptosis. Dipyridamole also duplicated the biochemical changes and apoptosis in glioma T98G cells. Since dipyridamole has additional biochemical and pharmacological properties, further research centered on the anti-glioma mechanisms of dipyridamole is still needed.
Highlights
Glioma is the most common type of primary brain tumor, with the worst and most aggressive type of glioma being glioblastoma multiforme
To extend the scope of anti-glioma studies regarding the cyclic Adenosine Monophosphate (cAMP) signaling pathway, this study aimed to determine whether Endoplasmic Reticulum (ER) stress is a key component of apoptotic cell death in dipyridamole-treated glioma cells, as well as identifying any downstream surrogates which may contribute to the apoptotic program
Our findings reveal that a reduction of Yes-associated Protein 1 (YAP1) due to dipyridamole, involving the ER stress-mediated phosphorylatory mechanism, leads to impaired autophagic flux and augmented apoptosis in glioma cells
Summary
Glioma is the most common type of primary brain tumor, with the worst and most aggressive type of glioma being glioblastoma multiforme. Glioblastoma multiforme, shows highly proliferative, angiogenic, infiltrative, and invasive phenotypes. Their multiforme phenotypes are treatment obstacles for successful surgical resection and causes of high recurrence rates [1,2]. Despite multimodal treatments and novel therapy being progressively developed, the clinical benefits of glioma patient treatment still remain unsatisfactory. The median survival period for patients with malignant glioma is approximately 1–2 years, with a 5-year survival rate of around 5–13% [3]. Advances in the elucidation of carcinogenic mechanisms, as well as developments of new compounds and novel therapeutic approaches targeting malignant glioma, are in high demand
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