Phosphoinositide-3-kinase inhibition elevates ferritin level resulting depletion of labile iron pool and blocking of glioma cell proliferation.
Adenine
/ analogs & derivatives
Animals
Brain Neoplasms
/ metabolism
Cell Proliferation
/ drug effects
Cells, Cultured
Chromones
/ pharmacology
Down-Regulation
/ drug effects
Ferritins
/ drug effects
Glioma
/ metabolism
Humans
Iron
/ metabolism
Morpholines
/ pharmacology
Phosphoinositide-3 Kinase Inhibitors
Pyrimidinones
/ pharmacology
Quinazolines
/ pharmacology
Rats
Thiazolidinediones
/ pharmacology
Up-Regulation
/ drug effects
Cell proliferation
Ferritin
Glioma
Iron regulatory protein
Labile iron pool
Phosphoinositide-3-kinase
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
20
08
2018
revised:
19
12
2018
accepted:
20
12
2018
pubmed:
27
12
2018
medline:
5
11
2019
entrez:
27
12
2018
Statut:
ppublish
Résumé
Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far. Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes. Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors. PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes. This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.
Sections du résumé
BACKGROUND
Elevated endogenous phosphoinositide-3-kinase (PI3K) activity is critical for cell proliferation in gliomas. Iron availability is one of the essential factors for cell growth and proliferation. However, any relation between PI3K and cellular iron homeostasis has not been understood so far.
METHODS
Glioma cells and human primary astrocytes were treated with class I PI3K inhibitors to examine regulation of iron homeostasis components. Regulation of ferritin was detected at mRNA and translational level. Labile iron pool (LIP) and cell proliferation were examined in glioma cells and human primary astrocytes.
RESULTS
Blocking of PI3K activity elevated ferritin level by 6-10 folds in glioma cells by augmenting mRNA expression of ferritin subunits and also by influencing ferritin translation. IRE-IRP interaction was affected due to conversion of IRP1 to cytosolic aconitase that was influenced by increased iron-sulfur scaffold protein iron-sulfur cluster assembly enzyme (ISCU) level. Elevated ferritin sequestered LIP to affect cell proliferation that was reversed in silencing ferritin by siRNAs of ferritin-H and ISCU. Human primary astrocyte with little PI3K activity did not show any change in ferritin level, LIP and cell proliferation by PI3K inhibitors.
CONCLUSIONS
PI3K inhibition promotes ferritin synthesis by dual mechanism resulting sequestration of iron to limit its availability for cell proliferation in glioma cells but not in primary astrocytes.
GENERAL SIGNIFICANCE
This observation establishes a relation between PI3K signalling and iron homeostasis in glioma cells. It also implies that activated PI3K controls ferritin expression to ensure availability of adequate iron required for cell proliferation.
Identifiants
pubmed: 30586625
pii: S0304-4165(18)30382-9
doi: 10.1016/j.bbagen.2018.12.013
pii:
doi:
Substances chimiques
5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione
0
Chromones
0
IC 87114
0
Morpholines
0
Phosphoinositide-3 Kinase Inhibitors
0
Pyrimidinones
0
Quinazolines
0
TGX 221
0
Thiazolidinediones
0
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
31M2U1DVID
Ferritins
9007-73-2
Iron
E1UOL152H7
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
547-564Informations de copyright
Copyright © 2018. Published by Elsevier B.V.