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- Title
Suppression of STAT3 and HIF-1 Alpha Mediates Anti- Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells.
- Authors
Jimin Shin; Hyo-Jeong Lee; Deok-Beom Jung; Ji Hoon Jung; Hyo-Jung Lee; Eun-Ok Lee; Seok Geun Lee; Beom Sang Shim; Seung Hoon Choi; Seong Gyu Ko; Kwang Seok Ahn; Soo-Jin Jeong; Sung-Hoon Kim
- Abstract
Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. Methodology/Principal Findings: BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1&agr; (HIF-1&agr;) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1&agr; and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia Conclusions/Significance: Taken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1a and STAT3 to the VEGF promoter in hypoxic PC-3 cells.
- Subjects
PROSTATE cancer treatment; CELLULAR signal transduction; CANCER cell proliferation; TRANSCRIPTION factors; NEOVASCULARIZATION; GENE expression; VASCULAR endothelial growth factors; GENE targeting; HYPOXEMIA; TRITERPENES; ANTINEOPLASTIC agents
- Publication
PLoS ONE, 2011, Vol 6, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0021492