title: Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells.
abstract: Increased expression and activation of receptor tyrosine kinases frequently occur in human brain tumors, mediating a variety of growth-promoting pathways and leading to radioresistance; however, little is known about their motogenic potency relative to one another. In this study, we found co-expression of Insulin like growth factor-1 receptor (IGF-1R) and platelet derived growth factor receptor (PDGFR) in two high-grade gliomas (HGG) cell lines 18 and 38. Dual targeting of IGF-1R and PDGFR increased cell death in both 18 and 38 cell lines in comparison to inhibition of either receptor alone. In addition, co-inhibition of IGF-1R and PDGFR increased radiosensitivity in 18 cells but failed to intensify the effect of radiation in 38 cells. In HGG cells, radiation-induced cell death has been connected to the activation of c-Jun-NH2-terminal kinase-1 (JNK1). We found that JNK1 was weakly expressed in 38 cells while it had an elevated expression in 18 cells. Exposure to ionizing radiation induced JNK1 activation only in 18 cells without affecting the protein activity in 38 cells. These results suggest that in 18 cell line radiation-activated JNK1 may provide an anti-proliferative signaling, parallel to receptors co-targeting. To test this hypothesis, HGG cells were treated with dominant negative JNK1 (dnJNK1) and the response to radiation was assayed in presence or absence of receptors co-inhibition. Indeed dnJNK protected 18 cells against gamma-irradiation-induced cell death. dnJNK treatment did not influence radiation response of the 38 cell line, which expressed low levels of JNK1. In conclusion we found that IGF-1R and PDGFR co-inhibition caused an increased cell death in two HGG cell line and induced the radiosensitization of the JNK1 expressing cell line.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska and Radiumhemmet Karolinska Institute/University Hospital, R8:00, Stockholm 171 76, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Carapancea
authors.forename: Daria
authors.initials: D
authors.lastname: Cosaceanu
authors.forename: Raluca
authors.initials: R
authors.lastname: Budiu
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiecinska
authors.forename: Ligia
authors.initials: L
authors.lastname: Tataranu
authors.forename: Vasile
authors.initials: V
authors.lastname: Ciubotaru
authors.forename: Oana
authors.initials: O
authors.lastname: Alexandru
authors.forename: Monica
authors.initials: M
authors.lastname: Banita
authors.forename: Catalina
authors.initials: C
authors.lastname: Pisoschi
authors.forename: Magnus L
authors.initials: ML
authors.lastname: Bäcklund
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.forename: Anica
authors.initials: A
authors.lastname: Dricu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004338:Drug Combinations; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000008:administration & dosage
chemical_list: D004338:Drug Combinations; D011838:Radiation-Sensitizing Agents; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D017526:Receptor, IGF Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D048055:Mitogen-Activated Protein Kinase 8