Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells.
Animals
Antineoplastic Agents
/ pharmacology
Biphenyl Compounds
/ pharmacology
Cell Proliferation
Glioblastoma
/ drug therapy
Hedgehog Proteins
/ metabolism
Humans
Imidazoles
/ pharmacology
Mice
Mice, SCID
Neoplastic Stem Cells
/ drug effects
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt
/ metabolism
Pyridines
/ pharmacology
Quinolines
/ pharmacology
Signal Transduction
/ drug effects
Smoothened Receptor
/ antagonists & inhibitors
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Akt
Glioblastoma
Glioblastoma-initiating cells
NVP-BEZ-235
NVP-LDE-225
PI3K
Sonic hedgehog
mTOR
Journal
Molecular and cellular biochemistry
ISSN: 1573-4919
Titre abrégé: Mol Cell Biochem
Pays: Netherlands
ID NLM: 0364456
Informations de publication
Date de publication:
Apr 2019
Apr 2019
Historique:
received:
12
04
2018
accepted:
16
08
2018
pubmed:
27
9
2018
medline:
20
4
2019
entrez:
26
9
2018
Statut:
ppublish
Résumé
Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP-LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl-2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs.
Identifiants
pubmed: 30251117
doi: 10.1007/s11010-018-3448-z
pii: 10.1007/s11010-018-3448-z
doi:
Substances chimiques
Antineoplastic Agents
0
Biphenyl Compounds
0
Hedgehog Proteins
0
Imidazoles
0
Phosphoinositide-3 Kinase Inhibitors
0
Pyridines
0
Quinolines
0
SHH protein, human
0
SMO protein, human
0
Smoothened Receptor
0
sonidegib
0RLU3VTK5M
MTOR protein, human
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
dactolisib
RUJ6Z9Y0DT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
11-23Références
Dev Neurosci. 2000;22(1-2):139-53
pubmed: 10657706
Nature. 2000 Apr 13;404(6779):782-7
pubmed: 10783894
Glia. 2001 Apr 1;34(1):1-7
pubmed: 11284014
Curr Opin Neurobiol. 2002 Feb;12(1):57-63
pubmed: 11861165
Nat Cell Biol. 2002 Sep;4(9):648-57
pubmed: 12172553
Development. 2003 Jan;130(1):15-28
pubmed: 12441288
Brain Pathol. 2003 Oct;13(4):507-18
pubmed: 14655756
Development. 2004 Jan;131(1):217-28
pubmed: 14660435
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
Nat Rev Mol Cell Biol. 2005 Apr;6(4):306-17
pubmed: 15803137
J Cell Sci. 2005 Dec 15;118(Pt 24):5675-8
pubmed: 16339964
Cell Mol Life Sci. 2006 Jun;63(11):1249-65
pubmed: 16596340
Cell Cycle. 2006 Oct;5(20):2301-5
pubmed: 17102612
Nature. 2007 Jan 4;445(7123):111-5
pubmed: 17122771
Curr Biol. 2007 Jan 23;17(2):165-72
pubmed: 17196391
Am J Pathol. 2007 Jan;170(1):347-55
pubmed: 17200206
Neuro Oncol. 2007 Jul;9(3):271-9
pubmed: 17504928
J Neurooncol. 2008 Jan;86(1):31-45
pubmed: 17611714
Acta Neuropathol. 2007 Aug;114(2):97-109
pubmed: 17618441
Trends Cell Biol. 2007 Sep;17(9):438-47
pubmed: 17845852
Cancer Res. 2008 Apr 1;68(7):2241-9
pubmed: 18381430
Nature. 2008 Apr 3;452(7187):650-3
pubmed: 18385740
Mol Cancer Ther. 2008 Jul;7(7):1851-63
pubmed: 18606717
Stem Cells. 2008 Dec;26(12):3018-26
pubmed: 18787206
Genes Dev. 2008 Sep 15;22(18):2454-72
pubmed: 18794343
N Engl J Med. 2009 Sep 17;361(12):1173-8
pubmed: 19726761
J Mol Med (Berl). 2009 Nov;87(11):1105-10
pubmed: 19816664
PLoS One. 2010 Dec 14;5(12):e15288
pubmed: 21179458
PLoS One. 2011 Jan 31;6(1):e16530
pubmed: 21304978
Cancer Res. 2011 Nov 15;71(22):7061-70
pubmed: 21975935
Cancer Biol Ther. 2012 May;13(7):487-95
pubmed: 22406999
Cancer Cell. 2012 Mar 20;21(3):374-87
pubmed: 22439934
Biochim Biophys Acta. 2012 Dec;1826(2):338-49
pubmed: 22677165
PLoS One. 2012;7(8):e43119
pubmed: 22900095
Oncol Rep. 2013 Mar;29(3):1124-32
pubmed: 23292285
Neuro Oncol. 2013 Jun;15(6):691-706
pubmed: 23482671
Oncotarget. 2013 May;4(5):665-76
pubmed: 23714687
Nat Med. 2013 Nov;19(11):1518-23
pubmed: 24076665
ACS Med Chem Lett. 2010 Mar 16;1(3):130-4
pubmed: 24900187
Oncotarget. 2014 Dec 15;5(23):12151-65
pubmed: 25432075
Med Oncol. 2015 Jan;32(1):368
pubmed: 25432698
PLoS One. 2015 Mar 16;10(3):e0116390
pubmed: 25775002
Oncotarget. 2015 Oct 13;6(31):32039-60
pubmed: 26451606
CA Cancer J Clin. 2017 Jan;67(1):7-30
pubmed: 28055103
Br J Cancer. 1997;76(2):141-5
pubmed: 9231911
Oncogene. 1997 Jul 17;15(3):361-6
pubmed: 9233770
Science. 1997 Aug 22;277(5329):1109-13
pubmed: 9262482
J Neurosci. 1997 Nov 1;17(21):8300-12
pubmed: 9334405