The pro-apoptotic Bcl-2 family member Harakiri (HRK) induces cell death in glioblastoma multiforme.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
2019
2019
Historique:
received:
08
10
2018
accepted:
07
11
2018
entrez:
19
2
2019
pubmed:
19
2
2019
medline:
19
2
2019
Statut:
epublish
Résumé
Harakiri (HRK) is a BH3-only protein of the Bcl-2 family and regulates apoptosis by interfering with anti-apoptotic Bcl-2 and Bcl-xL proteins. While its function is mainly characterized in the nervous system, its role in tumors is ill-defined with few studies demonstrating HRK silencing in tumors. In this study, we investigated the role of HRK in the most aggressive primary brain tumor, glioblastoma multiforme (GBM). We showed that HRK is differentially expressed among established GBM cell lines and that HRK overexpression can induce apoptosis in GBM cells at different levels. This phenotype can be blocked by forced expression of Bcl-2 and Bcl-xL, suggesting the functional interaction of Bcl-2/Bcl-xL and HRK in tumor cells. Moreover, HRK overexpression cooperates with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a known tumor-specific pro-apoptotic agent. Besides, secondary agents that augment TRAIL response, such as the histone deacetylase inhibitor MS-275, significantly increases HRK expression. In addition, GBM cell response to TRAIL and MS-275 can be partly abolished by HRK silencing. Finally, we showed that HRK induction suppresses tumor growth in orthotopic GBM models in vivo, leading to increased survival. Taken together, our results suggest that HRK expression is associated with GBM cell apoptosis and increasing HRK activity in GBM tumors might offer new therapeutic approaches.
Identifiants
pubmed: 30774992
doi: 10.1038/s41420-019-0144-z
pii: 144
pmc: PMC6368544
doi:
Types de publication
Journal Article
Langues
eng
Pagination
64Déclaration de conflit d'intérêts
The authors declare that they have no conflict of interest.
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