title: Adenovirus-mediated delivery of bFGF small interfering RNA reduces STAT3 phosphorylation and induces the depolarization of mitochondria and apoptosis in glioma cells U251.
abstract: Glioblastoma multiforme (GBM) carries a dismal prognosis primarily due to its aggressive proliferation in the brain regulated by complex molecular mechanisms. One promising molecular target in GBM is over-expressed basic fibroblast growth factor (bFGF), which has been correlated with growth, progression, and vascularity of human malignant gliomas. Previously, we reported significant antitumor effects of an adenovirus-vector carrying bFGF small interfering RNA (Ad-bFGF-siRNA) in glioma in vivo and in vitro. However, its mechanisms are unknown. Signal transducer and activator of transcription 3 (STAT3) is constitutively active in GBM and correlates positively with the glioma grades. In addition, as a specific transcription factor, STAT3 serves as the convergent point of various signaling pathways activated by multiple growth factors and/or cytokines. Therefore, we hypothesized that the proliferation inhibition and apoptosis induction by Ad-bFGF-siRNA may result from the interruption of STAT3 phosphorylation. In the current study, we found that in glioma cells U251, Ad-bFGF-siRNA impedes the activation of ERK1/2 and JAK2, but not Src, decreases IL-6 secretion, reduces STAT3 phosphorylation, decreases the levels of downstream molecules CyclinD1 and Bcl-xl, and ultimately results in the collapse of mitochondrial membrane potentials as well as the induction of mitochondrial-related apoptosis. Our results offer a potential mechanism for using Ad-bFGF-siRNA as a gene therapy for glioma. To our knowledge, it is the first time that the bFGF knockdown using adenovirus-mediated delivery of bFGF siRNA and its potential underlying mechanisms are reported. Therefore, this finding may open new avenues for developing novel treatments against GBM.
authors: Graduate school, Tianjin Medical University (22# Qixiangtai road Hexi District), Tianjin(300070), China.
authors: Jun
authors: J
authors: Liu
authors: Xinnv
authors: X
authors: Xu
authors: Xuequan
authors: X
authors: Feng
authors: Biao
authors: B
authors: Zhang
authors: Jinhuan
authors: J
authors: Wang
mesh_terms: D000256:Adenoviridae; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016222:Fibroblast Growth Factor 2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3