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ONX-0914 Induces Apoptosis and Autophagy with p53 Regulation in Human Glioblastoma Cells
SIMPLE SUMMARY: ONX-0914 (PR957) is a proteasome subunit beta type-8 (PSMB8)-selective inhibitor. Previous studies have shown that inhibiting PSMB8 expression in a glioblastoma reduces tumor progression and angiogenesis. This study shows that ONX-0914 inhibits glioblastoma cell proliferation and ind...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688407/ https://www.ncbi.nlm.nih.gov/pubmed/36428804 http://dx.doi.org/10.3390/cancers14225712 |
Sumario: | SIMPLE SUMMARY: ONX-0914 (PR957) is a proteasome subunit beta type-8 (PSMB8)-selective inhibitor. Previous studies have shown that inhibiting PSMB8 expression in a glioblastoma reduces tumor progression and angiogenesis. This study shows that ONX-0914 inhibits glioblastoma cell proliferation and induces cell death through apoptosis and autophagy via p53. In a mouse xenograft model, TMZ-combined ONX-0914 reduced tumor progression. This is the first study to evaluate the ONX-0914 function in glioblastomas. ABSTRACT: Glioblastoma is believed to be one of the most aggressive brain tumors in the world. ONX-0914 (PR957) is a selective inhibitor of proteasome subunit beta type-8 (PSMB8). Previous studies have shown that inhibiting PSMB8 expression in glioblastoma reduces tumor progression. Therefore, this study aimed to determine whether ONX-0914 has antitumor effects on human glioblastoma. The results indicated that ONX-0914 treatment inhibited survival in LN229, GBM8401, and U87MG glioblastoma cells. Cell cycle analysis showed that ONX-0914 treatment caused cell cycle arrest at the G1 phase and apoptosis in glioblastoma cells. The protein expression of BCL-2 was reduced and PARP was cleaved after ONX-0914 treatment. Furthermore, the levels of p53 and phosphorylated p53 were increased by ONX-0914 treatment in glioblastoma cells. ONX-0914 also induced autophagy in glioblastoma cells. Furthermore, the p53 inhibitor pifithrin attenuated apoptosis but enhanced autophagy caused by ONX-0914. In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma. |
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