Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells.
Cell death
Eye cancer
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
2020
2020
Historique:
received:
16
03
2020
revised:
26
03
2020
accepted:
28
03
2020
entrez:
28
4
2020
pubmed:
28
4
2020
medline:
28
4
2020
Statut:
epublish
Résumé
To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.
Identifiants
pubmed: 32337074
doi: 10.1038/s41420-020-0259-2
pii: 259
pmc: PMC7165182
doi:
Types de publication
Journal Article
Langues
eng
Pagination
22Informations de copyright
© The Author(s) 2020.
Déclaration de conflit d'intérêts
Conflict of interestThe authors declare that they have no conflict of interest.
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