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Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2006 Jul; Vol. 208 (1), pp. 220-8. - Publication Year :
- 2006
-
Abstract
- The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. The effects of the PDGFR inhibitor STI571 on proliferation and PDGFR signaling were compared in chemosensitive and cisplatin-selected, chemoresistant sublines derived from glioma and from two other PDGFR-expressing tumors (ovarian carcinoma and neuroblastoma). The chemoresistant glioma U87/Pt cells were twofold more sensitive to STI571 growth-inhibitory effects than the chemosensitive U87 cells, and two- to threefold more sensitive than five unrelated glioma cell lines. The other two paired cell lines were equally responsive. Sensitization of U87/Pt cells correlated with upregulation of the PDGF-B isoform and with PDGF-BB-induced Akt overactivation, which was prevented by STI571. STI571 specifically inhibited PDGF-BB-, but not PDGF-AA- or stem cell factor-mediated signaling. In serum-containing medium, STI571 decreased phospho-Akt in U87/Pt cells, but not in U87, while activating extracellular signal-regulated kinase (Erk) in both. STI571 antiproliferative effects were partially reverted by constitutively active Akt. Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.<br /> (Copyright 2006 Wiley-Liss, Inc.)
- Subjects :
- Becaplermin
Benzamides
Blotting, Western
Cell Line, Tumor
Cell Proliferation drug effects
Drug Resistance, Neoplasm physiology
Enzyme Activation drug effects
Enzyme Activation physiology
Female
Gene Expression Regulation, Neoplastic physiology
Glioma chemistry
Glioma physiopathology
Humans
Imatinib Mesylate
Mitogen-Activated Protein Kinase 3 analysis
Mitogen-Activated Protein Kinase 3 physiology
Neuroblastoma chemistry
Neuroblastoma pathology
Neuroblastoma physiopathology
Ovarian Neoplasms chemistry
Ovarian Neoplasms pathology
Ovarian Neoplasms physiopathology
Phosphorylation drug effects
Platelet-Derived Growth Factor analysis
Platelet-Derived Growth Factor genetics
Proto-Oncogene Proteins c-akt analysis
Proto-Oncogene Proteins c-akt physiology
Proto-Oncogene Proteins c-sis
Receptors, Platelet-Derived Growth Factor analysis
Receptors, Platelet-Derived Growth Factor genetics
Receptors, Platelet-Derived Growth Factor physiology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction drug effects
Antineoplastic Agents pharmacology
Glioma pathology
Piperazines pharmacology
Platelet-Derived Growth Factor physiology
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Pyrimidines pharmacology
Receptors, Platelet-Derived Growth Factor antagonists & inhibitors
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9541
- Volume :
- 208
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 16575905
- Full Text :
- https://doi.org/10.1002/jcp.20659