Bruceine A induces cell growth inhibition and apoptosis through PFKFB4/GSK3β signaling in pancreatic cancer.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Blotting, Western
Cell Line, Tumor
Cell Proliferation
/ drug effects
Glycogen Synthase Kinase 3 beta
/ metabolism
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Microscopy, Fluorescence
Neoplasm Transplantation
Pancreatic Neoplasms
/ drug therapy
Phosphofructokinase-2
/ metabolism
Polymerase Chain Reaction
Quassins
/ pharmacology
Signal Transduction
/ drug effects
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (PubChem CID: 2723939)
1-Hydroxybenzotriazole (PubChem CID: 75771)
Biotin (PubChem CID: 171548)
Bruceine A
Bruceine A (PubChem CID: 160006)
Dimethylformamide (PubChem CID: 6228)
GSK3β
Glycolysis
N,N-Diisopropylethylamine (PubChem CID: 81531)
N-BOC ethylenediamine (PubChem CID: 187201)
PFKFB4
Pancreatic cancer
Trifluoroacetic acid (PubChem CID: 6422)
dichloromethane (PubChem CID: 6344)
tert-butyl bromoacetate (PubChem CID: 79177)
Journal
Pharmacological research
ISSN: 1096-1186
Titre abrégé: Pharmacol Res
Pays: Netherlands
ID NLM: 8907422
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
10
03
2021
revised:
29
04
2021
accepted:
30
04
2021
pubmed:
17
5
2021
medline:
5
2
2022
entrez:
16
5
2021
Statut:
ppublish
Résumé
Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 β (GSK3β) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3β, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3β-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer.
Identifiants
pubmed: 33992797
pii: S1043-6618(21)00242-5
doi: 10.1016/j.phrs.2021.105658
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
PFKFB4 protein, human
0
Quassins
0
bruceine A
25514-31-2
Phosphofructokinase-2
EC 2.7.1.105
GSK3B protein, human
EC 2.7.11.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105658Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.