Abstract
BackgroundSignal 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 FindingsBA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) 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-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia.Conclusions/SignificanceTaken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is one of STAT protein family and constitutively active in a wide range of human cancer cells [1]
Conclusions/Significance: Taken together, our results suggest that betulinic acid (BA) has anti-angiogenic activity by disturbing the binding of hypoxia-inducible factor-1a (HIF-1a) and STAT3 to the vascular endothelial growth factor (VEGF) promoter in hypoxic PC-3 cells
Hypoxia is a hallmark of solid tumors [15] and HIF-1a is a transcription factor that responses to hypoxia [16]
Summary
Signal transducer and activator of transcription 3 (STAT3) is one of STAT protein family and constitutively active in a wide range of human cancer cells [1]. Recent studies reported that STAT3 is activated in response to hypoxia, a common feature of various solid tumors [3,4]. Recent evidences suggest the anti-cancer effects of BA [7,8], anti-inflammatory [9] and anti-viral [10] activities via various signaling pathways such as epidermal growth factor receptor (EGFR) [11], hedgehog [12], signal transducer and activator of transcription 3 (STAT3) [13] and nuclear factor-kappa B (NF-kB) [14]. 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
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