| dc.description.abstract | Specificity protein transcription factors (Sp1, Sp3 and, Sp4) and members of the orphan nuclear receptor 4A subfamily (NR4A1, NR4A2 and, NR4A3) are highly expressed in most solid tumors and their derived cell lines compared to corresponding non-tumor tissues. Several studies in our laboratory have shown that many anticancer agents including ROSinducers downregulate expression of Sp TFs in multiple cancer cell lines. We have also shown that NR4A1 acts as a cofactor for Sp1 or Sp4-mediated gene expression and CDIM/NR4A1 antagonists inhibited these responses in various cancer cell lines. The highly selective killing of cancer cell lines by piperlongumine is due to ROS-dependent epigenetic repression of c-Myc, which leads to downregulation of miRs 17, 20a, 27a, upregulation of ZBTB 4 and ZBTB10 which are Sp repressors and downregulate expression of Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated gene products. Sp TFs were also shown to be vital for the growth of multiple myeloma (MM) cells and similar results were observed after treatment of MM cells with bortezomib which is clinically used for treating this disease. Subsequent studies indicate that the underlying mechanism of action of bortezomib in MM cells is due to caspase-8 dependent downregulation of Sp TFs.
We also investigated the role of NR4A2 in glioblastoma cells and showed that knockdown of NR4A2 using antisense oligonucleotides inhibited growth, induced Annexin-V staining (apoptosis) and inhibited migration/invasion. Bis-indole derived NR4A2 ligands (C-DIMs) mimicked the functional responses observed in glioblastoma cells after NR4A2 knockdown indicating that NR4A2 ligands acts as NR4A2 antagonists and these compounds represent a novel approach for treating GBM. NR4A1 is overexpressed in both ER-positive and ER-negative breast cancers and high expression of NR4A1 predicts decreased patient survival and we demonstrated that NR4A1/Sp1 regulates the PD-L1 checkpoint ligand in TNBC cells and it can be decreased after treatment with CDIM/NR4A1 antagonists and enhance tumor immunity. Cl-OCH3, a buttressed CDIM 8 analog which acts as an immunotherapy mimic inhibited mammary tumor growth and decrease lung metastasis and increased Teff to Treg ratio compared to untreated mice. Thus CDIM/NR4A1 antagonist are novel small molecule immunotherapy mimics and checkpoint inhibitors that are being developed for clinical applications. | en |
