Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment.
Antineoplastic Agents, Alkylating
/ pharmacology
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
Chromones
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Enzyme Inhibitors
/ pharmacology
Gene Expression Regulation, Neoplastic
Glioblastoma
/ drug therapy
Humans
Membrane Potential, Mitochondrial
Morpholines
/ pharmacology
Necrosis
Phosphatidylinositol 3-Kinases
/ chemistry
Temozolomide
/ pharmacology
Tumor Cells, Cultured
ER stress
Hsp27
LY294002
gliomas
programmed death
temozolomide
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
13 May 2021
13 May 2021
Historique:
received:
09
03
2021
revised:
15
04
2021
accepted:
10
05
2021
entrez:
2
6
2021
pubmed:
3
6
2021
medline:
11
6
2021
Statut:
epublish
Résumé
The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment.
Identifiants
pubmed: 34068110
pii: ijms22105155
doi: 10.3390/ijms22105155
pmc: PMC8152763
pii:
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Biomarkers, Tumor
0
Chromones
0
Enzyme Inhibitors
0
Morpholines
0
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
31M2U1DVID
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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