Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy.

Details

Serval ID
serval:BIB_9E2BF43399E3
Type
Article: article from journal or magazin.
Collection
Publications
Title
Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy.
Journal
Lung Cancer
Author(s)
Fischer B., Frei C., Moura U., Stahel R., Felley-Bosco E.
ISSN
1872-8332 (Electronic)
ISSN-L
0169-5002
Publication state
Published
Issued date
2012
Volume
78
Number
1
Pages
23-29
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Malignant pleural mesothelioma (MPM) is a relatively chemoresistant malignancy. Diverse biological targets are under investigation to develop new therapeutic options. One of these targets, namely the phosphoinositide-3-kinase (PI3K) pathway, has been shown to be a regulator of the side population (SP) phenotype in different cancers. The SP phenotype is due to drug efflux abilities providing drug-resistant properties. The presence of a SP fraction in MPM was recently observed in our laboratory. The aim of this study was to investigate the role of the PI3K pathway in the regulation of the SP phenotype in MPM. Treatment of overnight serum-starved cells with IGF increased phosphorylation of downstream target AKT, S6 and 4EBP1 and SP fraction in ZL55, ZL34 and SDM103T2 MPM cell lines. The PI3K/mTOR inhibitor NVP-BEZ235 and PI3K inhibitor wortmannin reduced the phosphorylation of downstream target AKT, S6 and 4EBP1 and decreased the SP fraction. Chemotherapy resistance mediated by drug efflux was tested by treating the cells with mitoxantrone. NVP-BEZ235 increased mitoxantrone cytotoxicity and this effect was mimicked by fumitremorgin C, a specific ABCG2 inhibitor, although not to the same extent, indicating that ABCG2-mediated drug efflux participates to chemoresistance. The involvement of ABCG2 in drug efflux was confirmed by determination of ABCG2-mediated decrease of intracellular mitoxantrone accumulation and silencing experiments. NVP-BEZ235-mediated decrease in drug efflux was associated with a significant decrease of ABCG2 present at the cell surface in ZL55 and SDM103T2 cells. In conclusion, the PI3K pathway is playing an important role in regulating the SP phenotype in MPM cells and inhibition of this activity may contribute to a more efficient cancer treatment.
Keywords
ATP-Binding Cassette Transporters/metabolism, Androstadienes/pharmacology, Androstadienes/therapeutic use, Antineoplastic Agents/pharmacology, Antineoplastic Agents/therapeutic use, Cell Line, Tumor, Cell Membrane/metabolism, Drug Resistance, Neoplasm, Enzyme Inhibitors/pharmacology, Enzyme Inhibitors/therapeutic use, Glutamates/pharmacology, Guanine/analogs & derivatives, Guanine/pharmacology, Humans, Imidazoles/pharmacology, Imidazoles/therapeutic use, Mesothelioma/drug therapy, Mesothelioma/metabolism, Mitoxantrone/pharmacology, Neoplasm Proteins/metabolism, Phenotype, Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Phosphatidylinositol 3-Kinases/metabolism, Pleural Neoplasms/drug therapy, Pleural Neoplasms/metabolism, Protein Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/therapeutic use, Quinolines/pharmacology, Quinolines/therapeutic use, Side-Population Cells/metabolism, Signal Transduction/drug effects, TOR Serine-Threonine Kinases/antagonists & inhibitors
Pubmed
Web of science
Create date
12/08/2015 7:56
Last modification date
20/08/2019 15:04
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