Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo.
Acid sphingomyelinase
Kv1.3
Lysosomes
Mitochondria
Pancreas cancer
Sphingolipids
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
25
11
2022
accepted:
17
01
2023
revised:
12
01
2023
pubmed:
16
2
2023
medline:
28
3
2023
entrez:
15
2
2023
Statut:
ppublish
Résumé
Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic and flank pancreas cancers. Mechanistically, PAPTP and FTY-720 cause a disruption of both mitochondria and lysosomes, an alteration of mitochondrial bioenergetics and accumulation of cytoplasmic Ca
Identifiants
pubmed: 36790532
doi: 10.1007/s00109-023-02290-y
pii: 10.1007/s00109-023-02290-y
pmc: PMC10036429
doi:
Substances chimiques
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Sphingomyelins
0
Fingolimod Hydrochloride
G926EC510T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
295-310Subventions
Organisme : Worldwide Cancer Research
ID : 22-0348
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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