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

• Main Authors: Youfen Ma, Bixue Xu, Jia Yu, Lirong Huang, Xiaoping Zeng, Xiangchun Shen, Chunyan Ren, Yaacov Ben-David, Heng Luo
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: International Journal of Molecular Sciences
• Subjects: prostate cancer; fli-1 agonist; chalcone; invasion; migration; apoptosis
• Online Access: https://www.mdpi.com/1422-0067/21/6/2216

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 (<b>C10</b>), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of <b>C10</b> on the growth, metastasis, and invasion of PC3 cells in vitro. Our results show that <b>C10</b> exhibited a strong inhibitory effect on proliferation and metastasis of PC3 cells via several cellular and flow cytometric analyses. Further mechanism studies revealed that <b>C10</b> likely serves as an Fli-1 agonist for regulating the expression of Fli-1 target genes including phosphatidylinositol 3-kinase (<i>P110</i>), murine double minute2 (<i>MDM2</i>), B-cell lymphoma-2 (<i>Bcl-2</i>), Src homology-2 domain-containing inositol 5-phosphatase 1 (<i>SHIP-1</i>), and globin transcription factor-1 (<i>Gata-1</i>) as well as the phosphorylation of extracellular-regulated protein kinases 1 (<i>ERK1</i>). Further, we confirmed that C10 can regulate the expressions of vascular endothelial growth factor 1 (<i>VEGF-1</i>), transforming growth factor-β2 (<i>TGF-β2</i>), intercellular cell adhesion molecule-1 (<i>ICAM-1</i>), p53, and matrix metalloproteinase 1 (<i>MMP-1</i>) genes associated with tumor apoptosis, migration, and invasion. Thus, <b>C10</b> exhibits stronger anticancer activity with novel molecular targets and regulatory molecular mechanisms, indicating its great potency for development as a novel targeted anticancer drug.