Adenovirus-mediated delivery of bFGF small interfering RNA reduces STAT3 phosphorylation and induces the depolarization of mitochondria and apoptosis in glioma cells U251
Open Access
- 9 September 2011
- journal article
- Published by Springer Science and Business Media LLC in Journal of Experimental & Clinical Cancer Research
- Vol. 30 (1), 80-7
- https://doi.org/10.1186/1756-9966-30-80
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.Keywords
This publication has 38 references indexed in Scilit:
- Targeting SRC in glioblastoma tumors and brain metastases: Rationale and preclinical studiesCancer Letters, 2010
- Adenovirus-mediated delivery of bFGF small interfering RNA increases levels of connexin 43 in the glioma cell line, U251Journal of Experimental & Clinical Cancer Research, 2010
- The Role of Src in Solid TumorsThe Oncologist, 2009
- Persistently Activated Stat3 Maintains Constitutive NF-κB Activity in TumorsCancer Cell, 2009
- The Incidence, Correlation with Tumor-Infiltrating Inflammation, and Prognosis of Phosphorylated STAT3 Expression in Human GliomasClinical Cancer Research, 2008
- Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and AlkylatorsClinical Cancer Research, 2008
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Interleukin-6 gene amplification and shortened survival in glioblastoma patientsBritish Journal of Cancer, 2007
- The STATs of cancer — new molecular targets come of ageNature Reviews Cancer, 2004
- Activators and target genes of Rel/NF-κB transcription factorsOncogene, 1999