| dc.description.abstract | Nuclear receptor 4A1 (NR4A1) is an orphan receptor that is overexpressed in several cancers and is known for its pro-oncogenic activities in solid tumors. NR4A1 plays a crucial role in multiple cancers and regulates expression of important genes that are required for growth and proliferation (EGFR), migration and invasion (integrins), and survival (survivin) of cancer cells including rhabdomyosarcoma (RMS). Furthermore, NR4A1 also suppresses expression of interleukin-24 (IL-24) in RMS cells and IL-24 is an important gene that induces apoptosis and inhibits epithelial to mesenchymal transition (EMT). Thus, NR4A1 is an important target gene for cancer therapeutics and studies in our laboratory have developed a series of bis-indole derived molecules (CDIMs) that bind NR4A1 and act as NR4A1 antagonists in cancer cells. These antagonists inhibit NR4A1-regulated metabolic pathways in RMS and also inhibit the expression of NR4A1-regulated pro-oncogenic genes in RMS including the fusion oncogene PAX3-FOXO1. This makes NR4A1 a potential drug target in RMS chemotherapy. My studies were focused on the role of NR4A1 in regulating pro-oncogenic pathways and genes and on the mechanisms of these responses in RMS cells. I initially investigated the role of NR4A1 in TGFβ-induced embryonal RMS (ERMS) cell invasion and showed that NR4A1 antagonists inhibit invasion, which was due to a Bcl-2-NR4A1 complex activation responsible for mitochondrial disruption, IL-24 induction and β-catenin downregulation. I also examined the tumor promoting role of an important pro-oncogene G9a in alveolar RMS (ARMS) and showed that G9a is regulated by NR4A1 in ARMS. Furthermore, my studies have shown that NR4A1 antagonists are a novel class of G9a inhibitors. In addition, my studies have also characterized natural flavonoids kaempferol and quercetin as novel NR4A1 ligands and they inhibit NR4A1-regulated genes and pathways in RMS, and this includes PAX3- FOXO1 and G9a. These results suggest that flavonoids can be repurposed for RMS cancer therapy and thereby enhance the efficacy of current treatments and decrease their toxicity. Overall, I have identified novel NR4A1-regulated pro-oncogenic pathways in RMS and have shown that these pathways can be inhibited by treatment with NR4A1 antagonists that include flavonoids such as kaempferol and quercetin. | |
