Dopamine receptor D1 agonist inhibits glioblastoma via calpainmediated ER stress and mitochondrial dysfunction.
Oncol Rep
; 45(5)2021 05.
Article
em En
| MEDLINE
| ID: mdl-33760205
ABSTRACT
Recent studies have reported the important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). The present research aimed to explore the antineoplastic effect and intrinsic pathways of action of dopamine receptor D1 agonist SKF83959 on GBM cells. Flow cytometric analysis revealed a significant level of apoptotic cell death under SKF83959 treatment. SKF83959 administration increased intracellular calcium levels and oxidative stress through the phospholipase C/inositol trisphosphate pathway. The downstream calpains were activated and dysregulated by the increased calcium levels. The mitochondrial membrane potentialdependent staining assay revealed decreased mitochondrial transmembrane potential in GBM cells under SKF83959 treatment. The mitochondrial/cytosolic fraction and western blotting further demonstrated mitochondrial dysfunction and endoplasmic reticulum stress, followed by apoptosis. The calpain inhibitor, calpastatin, significantly reversed the increase in mitochondrial injury and endoplasmic reticulum stress and eventually ameliorated GBM cell apoptosis during SKF83959 treatment. Finally, the in vivo inhibitory efficacy of SKF83959 was verified in GBM xenograft models. In addition, immunohistochemistry and western blotting both revealed increased expression of calpains in xenograft GBM tissues. These results suggested a potential therapeutic target for human GBM treatment regarding calpain expression and activity regulation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
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Calpaína
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2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina
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Receptores de Dopamina D1
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Glioblastoma
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article