Fli-1 Activation through Targeted Promoter Activity Regulation Using a Novel 3’, 5’-diprenylated Chalcone Inhibits Growth and Metastasis of Prostate Cancer Cells

Abstract

The friend leukemia integration 1 (Fli-1) gene is involved in the expression control of key genes in multiple pathogenic/physiological processes, including cell growth, differentiation, and apoptosis; this implies that Fli-1 is a strong candidate for drug development. In our previous study, a 3′,5′-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3-pyridinyl)-propene-1-one (C10), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of C10 on the growth, metastasis, and invasion of PC3 cells in vitro. Our results show that C10 exhibited a strong inhibitory effect on proliferation and metastasis of PC3 cells via several cellular and flow cytometric analyses. Further mechanism studies revealed that C10 likely serves as an Fli-1 agonist for regulating the expression of Fli-1 target genes including phosphatidylinositol 3-kinase (P110), murine double minute2 (MDM2), B-cell lymphoma-2 (Bcl-2), Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1), and globin transcription factor-1 (Gata-1) as well as the phosphorylation of extracellular-regulated protein kinases 1 (ERK1). Further, we confirmed that C10 can regulate the expressions of vascular endothelial growth factor 1 (VEGF-1), transforming growth factor-β2 (TGF-β2), intercellular cell adhesion molecule-1 (ICAM-1), p53, and matrix metalloproteinase 1 (MMP-1) genes associated with tumor apoptosis, migration, and invasion. Thus, C10 exhibits stronger anticancer activity with novel molecular targets and regulatory molecular mechanisms, indicating its great potency for development as a novel targeted anticancer drug.

DNMT3b affects colorectal cancer development by regulating FLI1 through DNA hypermethylation

“…To fully appreciate the relevance of FLI1 to CRC, its biological significance as an inhibitor to colorectal pathogenesis should also be considered. FLI1 as a specific target for anti‐cancer drugs can regulate the proliferation and apoptosis of cancer cells and block the formation of tumor blood vessels for controlling cancer cell invasion and migration 24 . Our functional experiments provided convincing evidence to support the correlation of FLI1 with an inhibited phenotype, in which FLI1 overexpression suppressed CRC cell colony formation, migration, and invasion, but promoted apoptosis.…”

Chalcone Derivatives: Role in Anticancer Therapy

“…Ma et al found that a 3′,5′-diprenylated chalcone ( 61 , Figure 14 ) likely showed friend leukemia integration-1 (Fli-1) agonism and regulation of the expression of VEGF-1, TGF-β2, intercellular cell adhesion molecule-1 (ICAM-1), p53, and MMP-1 genes, which are associated with tumor apoptosis, migration, and invasion in prostate cancer cells [ 163 ]. Iheagwam et al performed a molecular docking analysis, also showing that flavonoids ( 62 ) isolated from young Caesalpinia bonduc twigs and leaves displayed strong interactions with TK, VEGF, and MMP [ 164 ].…”

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

“…VEGF receptor-2 (VEGFR-2) phosphorylates tyrosine at the Y658 and Y731 sites of VE-cadherin by inducing SRC family kinases, leading to destabilization of adherens junctions and increased endothelial cell permeability 28 , 29 . Youfen Ma et al found that the up-regulation of Fli-1 significantly inhibited VEGF expression 6 . In this experiment, both the LPS group and iri + LPS + apelin group showed similar results with low levels of Fli-1 with down-regulation of VE-cadherin, p-VE-cadherin, β-catenin and up-regulation of SRC, p-SRC, VEGF and VEGF-R.…”

“…Fli-1 is a transcription factor member of the ETS gene family, and it is mainly found in vascular endothelial cells, hematopoietic systems, immune cells and fibroblasts. A study found that Fli-1 regulates the expression of genes involved in the maintenance of vascular homeostasis, such as VEGF, platelet endothelial cell adhesion factor-1 (PECAM-1), VE-cadherin and S1P 6 , 7 . This suggests that the Fli-1 mediated endothelial cell homeostatic system plays an important regulatory role in vascular endothelial homeostasis, vascular skeleton formation and angiogenesis.…”